Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(O)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccc(Br)cc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: Oc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccc(Br)cc3)CS[C@H]12
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of (7R)-7-[(phenylacetyl)amino]-3-(4-bromophenylthio)-3-cephem-4-carboxylate, benzhydryl ester (80 mg, 0.12 mmol) in phenol (230 mg) at 45° was added trifluoroacetic acid (9 μL). After 1.5 h, the volatiles were removed with a rotary evaporator, and the residue was triturated with isopropanol/hexane. The resulting white solid was washed with ether and dried in vacuo, affording 48 mg (79%) of the title compound. 1H NMR (acetone-d6) δ3.67 (d, 1H, J=16), 3.75 (d, 1H, J=16), 3.64 (d, 1H, J=18), 3.67 (d, 1H, J=18), 5.25 (d, 1H, J=5), 5.92 (d, 1H, J=5), 7.2-7.7 (m, 9H); IR (KBr) 1347, 1386, 1606, 1756, 3276 cm-1.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH:19]([CH3:21])[CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH:19]([CH3:21])[CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl butanoate (602 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 43 (513 mg, 75% yield) as a white powder after work-up and mass-guided preparative HPLC purification. NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 11H), 1.17-1.38 (br. m, 3H), 1.48-1.58 (m, 2H), 1.65-1.73 (br. m, 2H), 1.83-1.98 (br. m, 3H), 2.10 (tt, J=12.0, 3.2 Hz, 1H), 2.21-2.32 (br. m, 2H), 2.75-2.87 (br. m, 2H), 6.44 (d, J=5.6 Hz, 1H), 7.40 (t, J=6.0 Hz), 11.97 (br. s, 1H). MS (EST) m/z 366.21 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38](=O)[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2/[C:38](=[CH:7]/[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1
Reactant: O=C1c2ccc(Br)cc2COc2ccccc21
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC/C=C1/c2ccc(Br)cc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane, and 8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an E/Z (1:3.5) isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z-isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 7.38-7.44 (m, 2H, H7 and H9); 7.13-7.18 (m, 3H, aromaatic H); 6.84-6.93 (m, 2H, H2 and H4); 5.70 (t, 1H, CH=); 5.15 (br s, 2H, ArCH2O); 2.55 (q, 2H, CH2); 2.43 (t, 2H, NCH2 ); 2.22 (s, 6H, NMe2).
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(CC)=O>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[CH:1][CH2:2][CH2:3][CH3:4])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: CCC(C)=O
Product: CCCC=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Reaction time: 4 h

Procedure:
A suspension of 13.5 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 100 cc of methylethyl ketone is heated at reflux while stirring for 4 hours. The title compound has a M.P. of 191°-193°, from 95% ethanol.
Reaction SMILES: C(C1C=NC(N2CCC(C[C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)CC2)=NC=1)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[CH:17][S:18][C:19]=3[CH:25]=2)[CH2:31][CH2:30]1
Reactant: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc3ncsc3c2)CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl 4-(2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (253 mg, 0.474 mmol) in DCM (4 mL) was added TFA (0.45 mL, 5.7 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (4 mL), washed with aq NaOH (1 N, 10 mL) and brine. The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford 2-O-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (206 mg, 0.451 mmol, 95% yield) as an off white solid. LCMS (m/z)=434 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([OH:16])[CH2:14][N:15]=2)=[CH:6][CH:5]=1)[CH3:2].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([O:16][C:30](=[O:31])[NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][N:15]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCSc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: CCSc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 12.3 %

Procedure:
A mixture of (5RS, 6SR)-2-[4-(ethylthio)phenyl]-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (6.5 g) and phenylisocyanate (2.6 g) in 1,2-dichloroethane (100 cc) is heated to a temperature in the region of 80° C. for 5 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is purified by chromatography on silica (0.063-0.2 mm; 150 g) contained in a column 3.5 cm in diameter eluting in 20-cc fractions with an ethylacetate/cyclohexane mixture (50:50 by volume). Fractions 5 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is further purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 3.5 cm in diameter, eluting in 25-cc fractions with a methylene chloride/methanol mixture (99:1 by volume). Fractions 10 to 18 are combined and concentrated to dryness under reduced pressure. (5RS, 6SR)-2-[4-(Ethylthio)phenyl]-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 70° C., is thereby obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37]>ClCCl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=4[CH3:34])=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.8 %

Procedure:
To a mixture of 0.362 g of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride and 0.101 g of triethylamine in 5 ml of dichloromethane is added a solution of 0.129 g of 2-methylaniline in 3 ml of dichloromethane. The mixture is stirred 1.5 hr at room temperature and then washed with H2O 1N HCl, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give a solid. The solid is dissolved in dichloromethane and filtered through a thin pad of hydrous magnesium silicate with dichloromethane as eluent to give 0.025 g of crystals, m.p. 214°-216° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[C:20]2[C:33]#N.[OH-].[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)=[C:20]2[C:33]1[NH:14][CH2:13][CH2:12][N:15]=1
Reactant: NCCN
Reactant: N#Cc1c(-c2cccc(F)c2)[nH]c2ccc(Cl)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-c2[nH]c3ccc(Cl)cc3c2C2=NCCN2)c1

Procedure:
Ethylendiamine tosylate (929 mg, 4.0 mmol) and 5-chloro-3-cyano-2-(3-fluorophenyl)-1H-indole (0.27 g, 1.0 mmol) were thoroughly mixed in a mortar and heated with melting at 320° C. for 10 min. After cooling it was stirred with a small amount of water, and the mixture was brought to pH9 with 2N sodium hydroxide. The precipitate was collected by filtration, washed with water, and dried in vacuo. The title imidazoline was isolated by chromatography on silica gel with dichloromethane/10% ethanolic ammonia 9:1 and recrystallized from methanol.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:4]([F:3])[C:5]([NH2:6])=[C:7]([F:11])[CH:8]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of bromine (127.0 g, 0.79 mol) in glacial acetic acid (200 ml) was added slowly, dropwise to a stirred solution of 2,6-difluoroaniline (101.5 g, 0.79 mol) in glacial acetic acid (550 ml) keeping the temperature below 25° C. The mixture was stirred at room temperature for 2 h, and then sodium thiosulphate (50 g), sodium acetate (125 g) and water (700 ml) were added and the mixture was cooled in a refrigerator overnight. The product was filtered off, dissolved in ether, and the ether phase was washed with water, 10% sodium hydroxide, water and dried (MgSO4). The solvent was removed in vacuo to yield a pale yellow solid (134 g) which was steam distilled to give a colourless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11](=[O:22])[N:12]([CH2:13][CH2:14][N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:8]=2[CH:7]=1)[CH3:4].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([S:35]([C:28]3[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[O:26][CH3:25])(=[O:37])=[O:36])[C:11](=[O:22])[N:12]([CH2:13][CH2:14][N:15]([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20])[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(CCN(C(C)C)C(C)C)c2c1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(CCN(C(C)C)C(C)C)c(=O)n2S(=O)(=O)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
0.05 g of sodium hydride as a 60% dispersion in oil is added in portions to a solution of 0.5 g of 5-ethoxy-1,3-dihydro-3-[2-(N,N-diisopropylamino)ethyl]-2H-benzimidazol-2-one in 7 ml of THF and the mixture is stirred for 30 minutes at RT. 0.42 g of 2,4-dimethoxybenzenesulfonyl chloride is then added and the mixture is stirred for 1 hour at RT. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 0.7 g of the expected product after crystallization from iso ether. M.p.=132° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([NH:10][C@H:11]([C@@H:29]([OH:31])[CH3:30])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[O:13][C:12]([C@H:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=4[CH3:32])[C@@H:29]([OH:31])[CH3:30])=[N:14][N:15]=3)=[CH:22][CH:21]=2)[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(-n3cccn3)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(-n4cccn4)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 1.17 h
Yield: 15.3 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(1H-pyrazol-1-yl)benzohydrazide (164 mg, 0.36 mmol) in anhydrous THF (12 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (495 mg, 1.09 mmol) followed by p-TSCl (83 mg, 0.44 mmol) and the mixture was stirred for 70 min. The mixture was filtered under suction and the residue washed with acetone (2×50 mL) followed by MeOH (2×50 mL). The filtrate was concentrated under reduced pressure to provide a off white solid, which was purified by flash chromatography over silica gel (25-50% EtOAc in hexanes) to provided 4-((1R,2S)-1-(5-(4-(1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile as a yellow oil (24 mg, 15%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.46 (d, J=2.5 Hz, 1H), 8.11 (dm, J=9.2 Hz, 2H), 8.06 (dm, J=9.0 Hz, 2H), 7.77 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.57 (dd, J=1.8, 2.5 Hz, 1H), 5.70 (d, J=8.6 Hz, 1H), 5.12 (dd, J=3.5, 8.6 Hz, 1H), 4.86 (br s, 1H), 4.69-4.60 (m, 1H), 2.41 (s, 3H), 1.42 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O.O>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate from step 1) (24.00 g, 92.57 mmol) and K2CO3 (15.35 g, 111.08 mmol) were dissolved in N,N-dimethylformamide (220 mL). 2,4-Difluorobenzyl bromide (20.12 g, 97.20 mmol) was then added and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with H2O (1 L) and the precipitate collected by filtration to afford a white solid (4.08 g, 11%). The resulting oil was purified by chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford an off white solid (11.88 g, 33%). The two solids were combined. 1H NMR (400 MHz, CDl3) δ 8.11 (dt, J=1.41, 7.79 Hz, 1H), 7.87 (app t, J=1.78 Hz, 1H), 7.58 (app t, J=7.69 Hz, 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, J=2.68 Hz, 1H), 5.90 (ddd, J=0.94, 1.74, 1.74 Hz, 1H), 5.97 (s, 1H), 3.90 (s, 3H), 1.89 (s, 3H). ES-HRMS m/z 386.1179 (M+H C21H17F2NO4 requires 386.1198).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.Br[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH:6]=[CH:5]2
Reactant: Oc1nccc2cc(Br)ccc12
Reactant: CC(Br)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(c1ccccc1)n1ccc2cc(Br)ccc2c1=O
Temperature: 70 °C
Yield: 100 %

Procedure:
6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and 1-bromoethylbenzene (160 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (7 mL) and treated with 50% aq. NaOH (2 mL) and the resulting mixture was stirred rapidly while heating to 70° C. After additional stirring for 14 hours, the mixture was diluted with diethyl ether and washed with water and brine. The organic phase was dried over Na2SO4. Addition of silica gel, concentration, and purification of the residue using flash silica gel chromatography (gradient 2→12% ethyl acetate/hexanes) gave 6-bromo-2-(1-phenylethyl)-isoquinolin-1-one (227 mg, 0.67 mmol, quant.) as a yellowish oil. This isoquinolinone (220 mg, 0.67 mmol) was converted, via Methods 1 and 2, to compound 4 (109 mg, 56%) and isolated as a white solid. [M−H]−=292.1 m/z. Activity: B
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](OC)(OC)OC>>[O:11]1[C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: COC(OC)OC
Reactant: Nc1cccc(C(=O)O)c1O
Product: O=C(O)c1cccc2ncoc12

Procedure:
A solution of 3-amino-2-hydroxy-benzoic acid (12.5 mmol) in trimethyl orthoformate (19.2 mL) is heated to reflux for 20 h and concentrated in vacuo. The residue is washed three times with hot MeOH, the filtrates are combined and the solvent is removed in vacuo to give the desired product which is used without further purification. 1H-NMR (DMSO-d6): δ=13.4 (bs, 1H); 8.87 (s, 1H); 8.08 (d, J=8.0 Hz, 1H); 7.96 (d, J=7.5 Hz, 1H); 7.52 (t, J=7.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
3-Cyanophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 min, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.33 g, 38%) as a white solid: mp 330-333° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.92 (t, J=5.5 Hz, 1H, NH), 7.32-7.65 (m, 6H, Ar), 7.93 (s, 1H, Ar), 9.00 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.55, 31.17, 39.67, 46.18, 51.57, 111.41, 118.91, 120.24, 121.59, 122.36, 124.64, 128.30, 130.02, 130.35, 131.63, 135.27, 139.92, 141.21, 154.98, 168.05, 171.00, 172.82; Anal. calcd. for C22H19N5O4+0.1H2O: C, 63.03; H, 4.62; N, 16.71. Found: C, 62.69, H, 4.48; N, 16.41.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20].S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[Na+]>>[CH3:19][O:18][C:16]([C:4]1[C:3]([Cl:20])=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:26]([O-:28])=[O:27])[C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=1)=[O:17]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)cc(N)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)cc(N)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-2-fluorophenyl)pyridine-2-carboxylate (1.0 g, 3.2 mmol) was added as a solid to well stirred concentrated sulfuric acid (16 mL) at 0° C. Sodium nitrate (0.29 g, 3.5 mmol) was added to the mixture and the resulting yellow solution was stirred at 0° C. for 1.5 hours then diluted with a large quantity of ice and allowed to warm to room temperature. The solution was filtered to remove some solids then the filtrate extracted with 3 portions of ethyl acetate and the combined ethyl acetate layers washed with saturated aqueous NaHCO3 and dried (Na2SO4). Filtration and concentration gave 4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)pyridine-2-carboxylic acid methyl ester (0.96 g, 2.7 mmol) as a yellow solid: mp 161-163° C.: 1H NMR (CDCl3): δ 8.73 (d, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 4.93 (bs, 2H), 4.02 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: O=c1[nH]sc2ccccc12
Product: CC1CCN(C(=O)Oc2nsc3ccccc23)CC1

Procedure:
In analogy to example 1, 45 mg (0.3 mmol) of benzo[d]isothiazol-3-one were reacted with 58 mg (0.36 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 26 mg (32%), M+H+: 277.14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([Li])CCC.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:17]2[CH:18]=[C:19]([F:21])[CH:20]=[CH:15][C:16]=2[C:22]2[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC1(C)COC(c2ccc(F)cc2F)=N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccc(F)cc2Sc2ccc(F)cc2)=N1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To 4-fluorothiophenol (9.26 g; 72.2 mmol.) in dry THF under nitrogen and cooled to -78° C. was added n-butyllithium (45.2 ml of 1.6M) dropwise affording a white slurry. To this mixture was added 2-(2,4-difluorophenyl)-4,4-dimethyloxazoline (7.63 g; 36.1 mmol.) in 20 ml of dry THF dropwise. The reaction mixture was allowed to warm to room temperature overnight. An additional 50 ml of THF was added to afford a solution and the reaction stirred over the weekend. The mixture was poured into water, acidified to pH 5 with 1N HCl. The mixture was extracted twice with diethyl ether and the organics combined, washed with water and then 0.2N NaOH. The organic layer was washed again with water and then brine, dried over MgSO4, and concentrated to afford 13.2 g of crude product which after recrystallization from hexane afforded 8.82 g of the subtitle compound.