Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:5])#[N:2].[CH3:16][C:17]([CH3:24])=[CH:18][C:19](OCC)=[O:20].CC(C)([O-])C.[K+].Cl>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:6]2[C:19](=[O:20])[CH2:18][C:17]([CH3:24])([CH3:16])[CH:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: N#CCC(=O)NCCc1ccc(F)cc1
Reactant: CCOC(=O)C=C(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CC1(C)CC(=O)N(CCc2ccc(F)cc2)C(=O)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 2-cyano-N-[2-(4-fluorophenyl)-ethyl]-acetamide (2.0 g, 19.4 mmol), ethyl 3-methylbut-2-enoate with a solution of potassium tert-butoxide in 80° C. After 16 hours, the mixture was cooled to room temperature and acidified with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to provide a brown solid. Recrystallization from 95% ethanol provided a tan solid (2.37 g, 85%). 1H NMR (300 MHz, dmso-d6) δ7.24 (m, 2H), 7.11 (t, J=9 Hz, 2H), 4.70 (s, 2H), 3.88 (m, 2H), 2.8-2.6 (m, 4H), 1.16 (s, 3H), 0.98 (s, 3H). Mass spec (ES−) m/z 287.2 (M−H−, 100%).
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4](=[O:30])[N:5]([CH3:29])/[C:6]/1=[CH:7]\[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1.[CH2:31](N)[C:32]#[CH:33]>C1(C)C=CC=CC=1>[F:27][C:25]([F:26])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][CH:8](/[CH:7]=[C:6]2/[C:2]([NH:1][CH2:33][C:32]#[CH:31])=[N:3][C:4](=[O:30])[N:5]/2[CH3:29])[CH2:9][CH2:10]1
Reactant: CN1C(=O)N=C(N)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCN
Solvent: Cc1ccccc1
Product: C#CCNC1=NC(=O)N(C)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of (5Z)-4-amino-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-1-methyl-1,5-dihydro-2H-imidazol-2-one (1.50 g) in toluene (10 mL) was added propargylamine (1.90 g) at room temperature. The reaction mixture was stirred at 100° C. overnight. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (870 mg).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH2:4][S:5](=O)[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl[Sn]Cl.C(Cl)(=O)C.O>CC#N.CN(C)C=O>[F:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Agent: Cl[Sn]Cl
Solvent: CC(=O)Cl
Solvent: O
Solvent: CC#N
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS[C@H]12
Reaction time: 1 h

Procedure:
To a solution of 2.08 g (3.7 mmole) of benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 15 ml CH3CN and 6 ml DMF (dimethylformamide) at 0° is added 0.765 g (4.04 mmole) of anhydrous SnCl2 and 1.21 g (15.4 mmole) of acetyl chloride and the resulting mixture is stirred at 0° for 1.0 hrs, then at 30° for 1.0 hour, and then poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with 3% HCl solution, 5% NaHCO3 solution, and water, and then dried (MgSO4) and stripped in vacuo to yield benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate, which can be purified by the method outlined in 3 above.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](O)=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](=[O:19])[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)NC1CC1

Procedure:
Cyclopropylamine was coupled with (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (8 g), EDC, HOBt, TEA in DMF to give 5 g of (2R,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white semi-solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[NH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>C(#N)C>[CH3:21][O:20][C:18]([CH2:17][N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:5][CH:4]=1)[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:19]
Reactant: COC(=O)CNCC(=O)OC
Reactant: ClCc1ccc(CCl)cc1
Solvent: CC#N
Product: COC(=O)CN(CC(=O)OC)Cc1ccc(CN(CC(=O)OC)CC(=O)OC)cc1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of α,α'-dichloro-p-xylene (87.5 g, 0.5 mol) in acetonitrile (300 ml) was added dimethyl iminodiacetate (328.7 g, 2.04 mols), and stirred at 65° to 70° C. for 8 hours. 250 ml of acetonitrile was added thereto, and crystals formed were removed by filtration, followed by concentrating the solution. After dissolving the residue in 600 ml of ethyl acetate, the solution was washed with water (400 ml×3), then concentrated. Recrystallization of the residue from a hexane-ethyl acetate mixture solvent gave the end product (170.0 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:24]([OH:26])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=1)=[O:5].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1[C:45]([NH:47][C@H:48](C(O)=O)CNC(=O)C1C=CC=CC=1[N+]([O-])=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC=C([N+]([O-])=O)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC([N+]([O-])=O)=CC=1)=O>>[Cl:1][C:2]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[O:32])[CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:24]([OH:26])=[O:25])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([N:47]([CH3:48])[CH3:45])=[CH:13][CH:12]=1)=[O:5]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)C(=O)O)c(Cl)c1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2[N+](=O)[O-])C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccc([N+](=O)[O-])c2)C(=O)O)c(Cl)c1
Product: CN(C)c1ccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)cc1

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]-amino]carbonyl]benzoyl]-3-(3,5-dinitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-nitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-nitrobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(4-nitrobenzoyl)amino-L-alanine),
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([C:19]2C=CC=CC=2)[CH:16]=[CH:15][C:14](C=O)=[CH:13][CH:12]=1.[OH-].[Na+].Cl>C(O)C.O>[C:11]1([CH:19]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 33 %

Procedure:
A solution of 4.92 g (36.1 mmol) of 2-hydroxyacetophenone, 3.30 g (34.2 mmol) of ,4'-(α-methyl)ethenyl, biphenyl 4-carboxaldehyde and 8.15 g NaOH (in 15 ml of water) in 100 ml of ethanol was stirred for 12 hours before the solution was poured into 400 ml of water. The resulting mixture was neutralized with dilute HCl to yield a chalcone. The yellow precipitate obtained was filtered and dried. The chalcone was purified by recrystallized from methylene chloride. Further oxidation of above chalcone was carried out with excess of H2O2 (30%) in ethanol under basic conditions for 12 hours. The resulting solution was poured into 500 ml water and acidified with dilute HCl. Yellow precipitate obtained was filtered and dried. Product was recrystallized form THF/hexane mixture. Yield: 33%. Quantum Yield: (1.8 relative to 3HF in methyl cyclohexane), Extinction coefficient: εmax (M-1 cm-1)=36000. λmax (abs)=355 nm and λmax (em )=550 nm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([NH:31][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12])[CH3:29]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethylamide (58 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 2-ethylamine (2 M in THF, 183 uL), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 436.6. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.44 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.81-7.65 (m, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.40-3.23 (m, 2H), 1.15 (t, 3H).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][CH2:13][CH2:14][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C@H:4]1[CH2:5]3.FC(F)(F)C(O)=O.[ClH:32].CCOCC>C(Cl)Cl.CCOCC.C(O)C>[ClH:32].[ClH:32].[CH:1]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][CH2:13][CH2:14][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:17][NH:16][CH2:15][C@H:4]1[CH2:5]3
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCOc4cccc(c43)[C@H]2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCO
Product: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To absolution of (+)-cis tert-butyl 6,7,9a,10,12,12a-hexahydro-5H-[1,4]oxazepino[2,3,4-ij]pyrrolo[3,4-c]quinoline-11(9H)-carboxylate (250 mg, 0.76 mmol) in 15 mL of methylene chloride was added trifluoroacetic acid (4 mL). This mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was basified with sat'd aq Na2CO3 and extracted with chloroform. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo to afford the free base. This material was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, basified with sat'd aq Na2CO3 and extracted twice with ethyl acetate. The organics were washed with brine, dried (Na2SO4) and concentrated to a free base. A portion of the residue (30 mg, 0.13 mmol) was taken up in about 4:1 ether/ethanol and then there was added 2M HCl in ether (0.2 mL, 0.39 mmol). The resulting solid was filtered, washed twice with ether and dried in vacuo to afford the title compound of EXAMPLE 121 as an off-white powder. 1H NMR (dmso-D6) δ: 9.52 (broad s, 1H), 9.30 (broad s, 1H), 6.90-6.83 (m, 1H), 6.75-6.70 (m, 2H), 4.60 (dt, 1H, J=12.0, 5.1 Hz), 3.77-3.63 (m, 2H), 3.52-3.45 (m, 1H), 3.40-3.25 (m, 2H), 3.19-3.06 (m, 2H), 3.05-2.85 (m, 2H), 2.84 (t, 1H, J=12.0 Hz), 2.65-2.55 (m, 1H), 2.08-1.97 (m, 1H), 1.90-1.79 (m, 1H). LRMS (ES)+: 231.0 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4].CO>O1CCCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4]
Reactant: CC#CCCC(=O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Reaction time: 1 h

Procedure:
At -40°, 420 mg. of sodium borohydride is added in incremental portions to a solution of 800 mg. of (1S,5R,6R,7R,3R)-7-acetoxy-6-[(E)-3-oxo-1-octen-6-ynyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 24 ml. of methanol and 10 ml. of tetrahydrofuran. The mixture is agitated for 1 hour at -40°. Then the mixture is gently combined with 1 ml. of glacial acetic acid, concentrated under vacuum, the residue combined with methylene chloride, the organic extract shaken with 4% sodium bicarbonate solution, washed neutral with water, dried with magnesium sulfate, and evaporated under vacuum. After chromatography of the residue on silica gel with ether/pentane (6+4), 250 mg. of the corresponding compound in the β-configuration is obtained, along with 266 mg. of the title compound as a colorless oil.
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][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=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.C(O)C>[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][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC(CO)Cc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.111 g, 0.204 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.428 ml, 0.428 mmol), and the reaction was stirred overnight. It was concentrated and then taken up in water. It was then acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 87 mg of the title compound (82.6% yield).
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[NH:7][C:6]=1[C:17]([NH:19][C:20]1[S:21][C:22]([CH3:25])=[CH:23][N:24]=1)=[O:18]>CO.[OH-].[Na+]>[CH2:1]([N:7]1[C:6]([C:17]([NH:19][C:20]2[S:21][C:22]([CH3:25])=[CH:23][N:24]=2)=[O:18])=[C:5]([OH:4])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8]1(=[O:16])=[O:15])[CH3:2]
Reactant: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2)s1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(C(=O)Nc2ncc(C)s2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
0.94 gm (6 millimols) of ethyl iodide were added to a solution of 0.7 gm (2 millimols) of 4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 30 ml of methanol and 2.0 ml of 1N sodium hydroxide. The reaction mixture was stirred for 24 hours at room temperature, then neutralized and evaporated in vacuo. The residue was purified by column chromatography (Merck-silica gel 60, particle size: 0.2-0.5 mm; eluant: chloroform/ethanol 95:5), yielding 0.35 mgm (48% of theory) of 2-ethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide after recrystallization from xylene.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>>[Br:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1ccc(CCBr)cc1

Procedure:
N-[4-(2-bromoethyl)benzoyl]methanesulfonamide was prepared according to Step 1 of Example 1 from methanesulfonamide and 4-(2-bromoethyl)-benzoyl chloride.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CCNCC
Product: CCN(CC)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and diethylamine (0.32 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-diethylamino-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (16 mg, 16%) as an off-white powder. ES-MS m/e calcd for C19H31N4O (M+H+) 331, found 331.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:27]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Reactant: OB(O)c1cncc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccccc3)c2)c2cccnc2n1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
150 mg 4-chloronaphthyridine from example 1, 184 mg 5-phenyl-3-pyridyl boronic acid, 326 mg sodium carbonate and 60 mg tetrakistriphenylphosphine palladium(0) were dissolved with 15 ml dioxan, flushed with nitrogen, and heated to 90° C. After addition of 2 ml water, heating continued at 90° C. for 90 minutes to give a dark turbid solution. Work-up as in example 20 yielded after precipitation with ether 141 mg product with correct LC mass: M+H+ 412 and Rt˜2.53 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:31]=[CH:30][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].NC1C=CC=CC=1.[F:39][C:40]([F:44])([F:43])[CH2:41]O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:29])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:27])[CH:21]=3)/[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:30][CH:31]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)O)ccc32)c2ccccc2)cc1
Reactant: OCC(F)(F)F
Solvent: Nc1ccccc1
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OCC(F)(F)F)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and 2,2,2-trifluoroethanol aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C27H24F3N3O3
Reaction SMILES: [CH2:1]([C:4]1[C:9](C(=O)N(C)C)=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=1[S-:17])[CH2:2][CH3:3].CO.C[O-].[Na+].Cl>CO>[CH2:1]([C:4]1[CH:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=1[SH:17])[CH2:2][CH3:3]
Reactant: CCCc1c([S-])ccc(C#N)c1C(=O)N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(C#N)ccc1S
Reaction time: 5 h

Procedure:
A mixture comprising 2.86 g of the thiophenolate thus obtained, 30 ml of dried methanol and 3.0 ml of a 28% sodium methoxide methanol solution, was stirred at room temperature for 15 hours. Then, 1.5 ml of a 28% sodium methoxide methanol solution was added, and the mixture was stirred for further 5 hours. The reaction mixture was acidified to a pH of about 2 by gradually adding concentrated hydrochloric acid thereto, and then the solvent was distilled off. Water was poured into the dark brown oily residue thus obtained, and the mixture was extracted with benzene. The benzene layer was washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a dark brown oily substance. The oily substance was purified by silica gel column chromatograph by using benzene-n-hexane (2:1, v/v) as the developer, whereby 1.13 g of the above identified compound was obtained as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([O:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:18]3=[O:44])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:24][N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:17]([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:46][CH:45]=3)=[CH:13][CH:12]=2)(=[O:16])=[O:15])[C:18]1=[O:44]
Reactant: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(O)C3=O)cc2)cc1
Reaction time: 0.5 h

Procedure:
3-[4-(4-Methoxy-phenoxy)-benzenesulfonyl]-1-trityloxy-azepan-2-one prepared from step G (3.2 mg, 0.00817 mmol) in 1.0 ml of anhydrous CH2Cl2 was added 1.0 ml of TFA and the resulting solution was stirred for 30 min. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜5% MeOH in CH2Cl2). MS: 391.8 (M+H)+, 413.9 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:6]=[CH:5]2.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][N:24]=[C:23]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C(Cc1ccccc1)Nc1ccc2cc(O)ccc2c1
Product: COc1cc2ncnc(Oc3ccc4cc(NC(=O)Cc5ccccc5)ccc4c3)c2cc1OC

Procedure:
N-(6-Hydroxy-2-naphthyl)-2-phenylacetamide from step (b) above (260 mg, 0.9 mmol) reacted with 4-chloro-6,7-dimethoxy-quinazoline (210 mg, 0.9 mmol, Oakwood) under the conditions of Example 4b to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 466.2 (M+1). Mass Calc'd for C28H23N3O4: 465.17.