Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:13]([CH:10]3[CH2:12][CH2:11]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: O=C(Cl)C1CC1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2nnc(C3CC3)n2c1
Temperature: 90 °C
Yield: 106.5 %

Procedure:
A mixture of 5-bromo-pyridin-2-yl-hydrazine (15.0 g, 79.8 mmol) and cyclopropane carbonyl chloride (65.0 mL, 71.8 mmol) is heated at 90° C. for 18 hours. The brown mixture is allowed to cool to room temperature, filtered, and washed with toluene to afford a light brown solid. This solid is taken up in chloroform (CHCl3), and washed with saturated NaHCO3. The organic layer is isolated, and the aqueous layer extracted twice with chloroform (CHCl3). The combined organics are washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a tan solid (18.2 g, 96%).
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.ClCCCl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2C(=O)C3(CCOCC3)N(CCCC(O)=O)[C:24]2=[O:40])=[CH:19][C:18]=1[C:41]([F:44])([F:43])[F:42])#[N:16]>C(N(CC)CC)C>[NH:10]=[C:9]1[C:2]2([CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[NH:1][C:24](=[O:40])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:41]([F:42])([F:43])[F:44])[CH:19]=1
Reactant: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Reactant: CN1CCC(N)(C#N)CC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Using the procedure of Stage 2 of Example 20, 153 mg of the product of Stage 1 of Example 20, 1.5 ml of 1,2-dichlorethane and 0.1 ml of triethylamine were reacted and the solution was placed in an ice-cooled water bath. 1 ml of the product of Example 7 of European Patent Application EP 0,494,819 was added and the mixture was allowed to return to ambient temperature. The reaction medium stood for one hour, was dried and the residue was purified on silica with methylene chloride-methanol: 7-3 as eluant to obtain 277 mg of the expected product (white crystals) melting at 199-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.[Br:11]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(OCC)C.O>[Br:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1]
Reactant: Brc1cccc2c1CC=C2
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: BrC1=Cc2cccc(Br)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Using a 200 ml Erlenmeyer flask, 7.00 g (35.89 millimoles) of 7-bromoindene produced by the method described in J. Org. Chem. 49, 4226–4237(1984) was dissolved in a mixed solvent of 1.42 g (79.00 millimoles) of distilled water and 70 ml of dimethyl sulfoxide. To this reaction solution there was added 7.67 g (43.07 millimoles) of N-bromosuccinimide while cooling on ice, and the mixture was then stirred for one hour at room temperature. After hydrolysis with distilled water while cooling on ice, extraction was performed several times with diethyl ether, and the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained product was transferred to a 200 ml Erlenmeyer flask and dissolved in 100 ml of toluene. To this solution there was added 0.68 g (3.59 millimoles) of p-toluenesulfonic acid hydrate, and the mixture was heated to reflux for 4 hours. After reflux, hydrolysis was performed with distilled water while cooling on ice, and extraction was performed several times with diethyl ether. The extract was washed once with a saturated sodium bicarbonate aqueous solution, washed once with saturated saline, and then dried over anhydrous magnesium sulfate. After drying, the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and purification was performed with a silica gel column to obtain 6.6 g of 2,7-dibromoindene as white crystals (67% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.75 g) is alkylated using ethyl iodide (0.5 ml; 5.7 mmol) and K2CO3 (1.6 g; 11.6 mmol) at 55° C. for 7 h. After aqueous work-up the crude alkylated acetamide (0.8 g; 2.74 mmol) is de-acetylated under reflux conditions in 2-propanol (3 ml) and hydrochloric acid (5 ml). After aqueous work-up the crude 5-amino-1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.6 g) is used without further purification.
Reaction SMILES: [CH2:1]([C:4]1([NH:14][NH2:15])[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.CN(C)[CH:25]=[CH:26][CH:27]=O>CC(O)C>[CH2:1]([C:4]1([N:14]2[CH:27]=[CH:26][CH:25]=[N:15]2)[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(NN)CCOC2(CCCC2)C1
Reactant: CN(C)C=CC=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reaction time: 48 h
Yield: 31 %

Procedure:
A solution of [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and 3-dimethylaminoacrolein. The solution was refluxed for 3 h and then at 50° C. for 2 d. The solvent removed and the residue was purified on 25 g Biotage snap column, eluted with 0-18% EtOAc in Hex (12 CV) to give 1-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]-1H-pyrazole (80 mg, 31% yield).
Reaction SMILES: [C:1](O[C:5](=[O:7])C)(=[O:3])C.[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14].CC(CC(O)=O)=O.[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C(O)=O>[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7].[CH:1]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:15])([OH:14])[OH:16])[OH:8])=[O:3].[CH2:24]([NH:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)CC(=O)O
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.5 h

Procedure:
Formic acid (2 ml.) was added dropwise to acetic anhydride (2.45 ml.) at ambient temperature with stirring. After the stirring was continued at the same temperature for 30 minutes, 3-(N-hydroxyamino)propylphosphonic acid (3.10 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for an hour and then concentrated under reduced pressure to give an oily residue, which was dissolved in water (25 ml.). To the aqueous solution was added dropwise a solution of diacetic acid salts of N,N'-dibenzylethylenediamine (3.60 g.) in water (15 ml.) under ice-cooling and with stirring. The resultant mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was dissolved in water (30 ml.). The aqueous solution was concentrated under reduced pressure to give an oily residue, which was crystallized with a mixture of methanol (30 ml.) and ethanol (40 ml.). The crystals were separated by filtration, washed with ethanol (20 ml.) and then dried to give crystals (3.34 g.). The same crystals (1.00 g.) were recovered from the filtrte and the washings by concentrating them under reduced pressure to a volume of 40 ml. and allowing the concentrate to stand overnight at 4° C. A part (3 g.) of the combined crystals, as obtained above, was recrystallized from a mixture of water and ethanol (1:6) (40 ml.) to give N,N'-dibenzylethylenediamine bis[3-(N-formyl-N-hydroxyamino)propylphosphonate] (2.60 g.) in the form of needles.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]=[O:15])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: Cc1nnc(N=C=O)s1
Reactant: CNCCC=O
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CCC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.[NH4+:25].[OH-].O1CCOCC1>O>[NH2:20][C:19]1[C:18]([F:24])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:25])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Temperature: 130 °C
Yield: 83.3 %

Procedure:
In a microwave reaction vessel 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (590 mg, 1.626 mmol) was combined with NH4OH 28-30% (15 mL, 385 mmol) and 1,4-dioxane (4 mL). The mixture was heated in the microwave for 40 min at 130° C. The crude product was then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried over Na2SO4. The organics were then filtered and concentrated to dryness. The crude material was dissolved in DCM (2 mL), injected onto the top of a silica gel column then purified using EtOAc and hexanes. Desired fractions were concentrated to dryness to yield the title compound of Step A as a beige powder (490 mg, 1.355 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=5.1 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 6.86 (t, J=8.2 Hz, 1H), 6.71 (s, 2H), 6.58 (t, J=6.2 Hz, 1H), 6.15 (d, J=5.1 Hz, 1H), 5.26 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.[Si:46]([O:63][CH:64]1[CH2:67][NH:66][CH2:65]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[Si:46]([O:63][CH:64]1[CH2:65][N:66]([C:1]([C:4]2[N:5]=[C:6]([N:9]3[CH2:10][CH:11]([S:13][C:14]4[C@H:15]([CH3:45])[C@@H:16]5[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)[S:7][CH:8]=2)=[O:3])[CH2:67]1)([C:59]([CH3:62])([CH3:60])[CH3:61])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)C5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 32.2 %

Procedure:
Subsequently, to a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.71 g, 2.53 mmol) and 3-t-butyldiphenylsilyloxyazetidine (947 mg, 3.04 mmol) (obtained as described above) in dimethylformamide (86 ml) were added diethylphosphoryl cyanide (461 μl, 3.04 mmol) and triethylamine (426 μl, 3.04 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 5.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (4:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (789 mg, yield 32%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3]1[N:30]=[C:28]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[S:29][CH:2]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(Nc2nc(-c3cc(Cl)ccc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 100.5 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 89 mg (0.33 mmol) 2-bromo-1-(2,5-dichlorophenyl)ethanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was stirred with diethyl ether and little ethanol to yield 130 mg (100%) [4-(2,5-dichloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 431.2/433.0 (100/66) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.80 (s, 1H), 9.29 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.15 (d, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:5]=[C:4]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:3]=1.[C:16]([Cu])#[N:17].O.CCOC(C)=O>CN(C=O)C>[OH:15][C:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[N:5]=1)[C:16]#[N:17])([CH3:14])[CH3:13]
Reactant: N#C[Cu]
Reactant: CC(C)(O)c1cc(Br)cc(C(C)(C)O)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1cc(C#N)cc(C(C)(C)O)n1
Reaction time: 20.5 h
Yield: 32.1 %

Procedure:
A solution of 1.45 g (5.28 mmol) of 2,2′-(4-bromopyridine-2,6-diyl)dipropan-2-ol and 585 mg (6.53 mmol) of CuCN in 20 mL of DMF was heated at 150° C. After about 20.5 h, 40 mL of H2O and EtOAc was added, and the mixture was filtered through a Buchner funnel. The layers were separated, and the organic layer was washed with water (3×30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 373 mg of 2,6-bis(2-hydroxypropan-2-yl)isonicotinonitrile as a pale orange solid in 32% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:16]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1.C([O:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C(N(CC)CC)C>CO>[N+:17]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:16][C:7]=1[O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:23](=[O:22])[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:14]1)([O-:19])=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)C(F)(F)F
Reaction time: 8 h

Procedure:
A reaction mixture of 0.071 g trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochlorid, 0.05 g ethyltrifluoroacetate and 0.075 g triethylamine in 2 ml methanol was stirred overnight. The mixture was concentrated and partitioned between 5 ml EtOAc and 5 ml water. The organic phase was washed with water, HCl solution (2M) and water. The organic phase was dried and the solvent evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1C=CC([I+][C:16]2[C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1>CO.[OH-].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: Cc1ccccc1O
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Oc1ccccc1C(=O)O
Temperature: 90 °C
Reaction time: 10 h
Yield: 64.6 %

Procedure:
A solution of 2-methylphenol (III: R3 =H) (33 g, 305 mmol) in MeOH (100 mL) was treated with Na (2.1 g, 90 mmol), and excess MeOH was removed under reduced pressure. Diphenyliodonium-2-carboxylate (II: R1 =H) (19.6 g, 60 mmol) and cupric acetate (0.5 g) were added and the mixture was stirred at 90° C. for 10 h. The solution was diluted with 2N NaOH, filtered through celite and acidified with HCl. The mixture was then dissolved in 2N K2CO3 and extracted twice with EtOAc to remove excess 2-methylphenol. The aqueous layer was then poured into excess 2N HCl to give 2-(2-methylphenoxy)benzoic acid (IV: R1 =R3 =H) (8.85 g, 64%), suitable for the next step. A sample crystallized from ligroin, mp 133°-134° C. (Ber, 1905, 38, 2111 records mp 133.5° C.).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1cccc(Cl)c1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-chloroaniline (31 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-20% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-chlorophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 24 mg (23%). 1H-NMR: 10.60 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.93 (t, J=2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.66 (ddd, J=8.5, 2.0, 1.0 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.12-7.07 (m, 2H), 3.86-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:23][CH2:24][Cl:25])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cc1cccc(OCCCl)c1
Yield: 92.9 %

Procedure:
To a stirred solution of 3-hydroxyphenylacetic acid methyl ester (22.6 g, 136 mmol) and 2-chloroethyl p-toluenesulfonate (40 g, 171 mmol) in 900 mL of acetone was added Cs2CO3 (88.8 g, 272 mmol) and the mixture was headed at reflux for 3 h. The reaction mixture was then cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0-7% EtOAc in hexanes to yield 28.9 g (90% yield) of [3-(2-chloroethoxy)phenyl]-acetic acid methyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of compound 4,6-dichloro-2-phenyl-pyrimidine (27 g, 112 mmol), 4-trifluoromethoxy aniline (21 g, 119 mmol) and triethylamine (33 mL, 225 mmol) in n-butanol (300 mL) was refluxed for 20 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The crude compound was passed through the silica gel by using 5-6% ethylacetate in petroleum ether to afford the compound (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (20 g, 46%) as off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=2)=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1cccc(F)c1
Product: O=C(CNC(=O)c1cccc(F)c1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 3-fluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5cccc(C)c5n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(8-methylquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.024 g, 0.0464 mmol) in 3:1 THF/MeOH (1 ml) was added 1M sodium hydroxide (0.0511 ml, 0.0511 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated to dryness and acidified with diluted hydrochloric acid. The reaction was extracted with EtOAc twice, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.02 g, 0.0409 mmol, 88.1% yield). MS (apci) m/z=489.1 (M+H).