Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]2[C:13]3[CH2:21][NH:20][CH2:19][CH2:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH3:10])=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[C:29]([CH:32]=1)[C:30]#[N:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([N:20]2[CH2:19][CH2:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C@@H:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][CH:5]=4)[CH3:10])[C:13]=3[CH2:21]2)=[C:29]([CH:32]=1)[C:30]#[N:31]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(c1ccc(Br)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Yield: 54.5 %

Procedure:
A mixture of (R)—N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (300 mg, 0.93 mmol), 5-bromo-2-fluorobenzonitrile (560 mg, 2.8 mmol), N,N-diisopropylethylamine (480 μL, 2.8 mmol), and acetonitrile (4 mL) was subjected to microwave irradiation at 180° C. for 2 h. More 5-bromo-2-fluorobenzonitrile (500 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. Additional 5-bromo-2-fluorobenzonitrile (500 mg) was added and the mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. LC-MS indicated the amine was nearly completely consumed. After cooling the mixture was concentrated in vacuo, and the residue was purified by silica gel column (100% EtOAc) to yield a light yellow solid (255 mg, 54%).
Reaction SMILES: [N:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19](O)=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19]([NH:9][CH2:8][CH:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20]
Reactant: NCC(c1ccccn1)N1CCOCC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Cl)c(C(=O)NCC(c2ccccn2)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3 mmol), 2-chloro-5-methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC to yield the title compound (100 mg, yield: 90%). LCMS (Mt): m/z=360.0, tR (minutes, Method A)=0.89
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(C)c(CNN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(C)c(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
26.6 g of 2,5-dimethylbenzylhydrazine were added dropwise to a solution of 28.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 130 ml of ethanol, in the course of which the temperature rose from 25° to 35° C. After stirring overnight, the compound identified above separated out, and was filtered off and recrystallised from ethanol. Melting point: 124°, 20 g (52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([C:18]#[CH:19])[C:15]([CH3:20])=[N:14]1.[Br:21]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:21][C:19]#[C:18][C:16]1[C:15]([CH3:20])=[N:14][N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)4-ethynyl-3-methylpyrazole (0.53 g) in acetone (5 ml) was added N-bromosuccinimide (0.295 g) and silver nitrate (0.028 g). Stirring was continued at room temperature for 1 hour. The reaction mixture was evaporated and the residue taken up in ether and washed with water. The organic layer was separated, dried and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane and then dichioromethane: hexane (1:1). Combination and evaporation of appropriate fractions, followed by crystailisation from hexane, gave the title compound as a very pale yellow solid m.p. 86-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[CH3:43])[NH2:39]>CN(C=O)C.O>[CH3:35][C:36]1[CH:37]=[C:38]([NH:39][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:40]=[CH:41][C:42]=1[CH3:43]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-hydroxy-3-nitrobenzoic acid (732 mg), EDCI (768 mg) and HOBt (540 mg) in DMF (8 mL) was added 3,4-dimethylaniline (484 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was concentrated until crystallization occurred. The mixture was cooled to room temperature and the solid filtered, washed with EtOAc and dried under reduced pressure to give N-(3,4-dimethyl-phenyl)-4-hydroxy-3-nitrobenzamide as a pale-yellow solid, mp=209-212° C.; MS (m/z) 285 (M−1).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1cc(N)cc(OC)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc(OC)c1
Yield: 98 %

Procedure:
Prepared from VII and 3,5-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 98%; yellow solid; mp 248° C.; IR (KBr) νmax/cm−1 3242, 2940, 2837, 2223, 1711, 1647, 1578, 1455, 1419, 1383, 1357, 1306, 1265, 1205, 1144, 1058, 1046, 968, 943, 917, 833, 806; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 6.31 (m, 3H), 3.74 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C@@H:10]([CH3:13])[CH2:11][OH:12].C(OCC)(=O)C.CCCCCC>CO>[OH:12][CH2:11][C@@H:10]([N:9]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[CH3:6])[CH3:13]
Reactant: CC(=O)CCC(C)=O
Reactant: C[C@H](N)CO
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1[C@@H](C)CO
Yield: 96.3 %

Procedure:
2,5-Hexanedione (3.6 mL, 30.7 mmol) was added to a solution of (S)-2-amino-1-propanol (2.44 g, 32.5 mmol) in 15 mL of methanol. The mixture was stirred at reflux for 2 h. After concentrating in vacuo, the residue was dissolved in 100 mL of ethyl acetate and washed with 50 1 mL of saturated aqueous sodium bicarbonate and 50 mL of saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give a yellow solid. Flash column chromatography on 150 g of silica gel using 2.5 L of 15% ethyl acetate/hexane to furnish 4.53 g (96% yield) of (S)-1-(2-hydroxy-1-methylethyl)-2,5-dimethylpyrrole as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12](=[N:17][O:18][CH3:19])[C:13]([NH:15][CH3:16])=[O:14])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1cccc(-c2ccc(Cl)cc2)c1
Yield: 75.9 %

Procedure:
A solution of 13 g of the product from Example 7 in 105 ml of dimethoxyethane was admixed with 9.9 g of 4-chlorophenylboronic acid, 6.7 g of sodium carbonate, 34 ml of water and 200 mg of tetrakis(triphenylphosphine)palladium(0) and refluxed for 3 hours. The mixture was then poured into water and extracted with ethyl acetate, and the extract was washed with 1N aqueous sodium hydroxide solution and then with water and dried. Distillative removal of the solvent and silica gel chromatography (MtBE: cyclohexane=9:1) gave 9.5 g of product as colorless crystals of m.p. 118-121° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reactant: Nc1ccnc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)c2)c2ccccc12
Reaction time: 18 h
Yield: 40.6 %

Procedure:
2-Morpholin-4-yl-pyridin-4-ylamine (159 mg, 0.88 mmol) and (4-Bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (260 mg, 0.89 mmol) were suspended in 6 mL toluene/Dioxane 1/1 and Pd(OAc)2 (6 mg, 3 mol %), BINAP (27 mg, 5 mol %) and CS2CO3 (858 mg, 2.64 mmol) were added. The reaction mixture was stirred from 80° C. to 80° C. over 18 hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 140 mg of product. This product was subjected to the methods described previously to obtain the final compounds of interest.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH3:26])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:22][C:21]=2[CH3:26])=[O:19])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Agent: Cl
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 99 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use isonicotinoyl chloride hydrochloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide, the title compound was obtained as a white solid in 99% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.75-8.73 (m, 2H), 7.95-7.93 (m, 2H), 7.34 (s, 2H), 7.31 (s; 2H), 4.86 (s, 2H), 2.54 (s, 3H); MS (ES+) m/z 387.0 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13].[OH2:16]>N1C=CC=CC=1>[C:1]([NH:10][NH:11][C:12]([NH:14][NH:15][C:1](=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=S)NN
Reactant: O
Solvent: c1ccncc1
Product: O=C(NNC(=S)NNC(=O)c1ccccc1)c1ccccc1

Procedure:
116 ml of benzoyl chloride are added dropwise at a temperature of 25° C. to a suspension of 53 g of thiocarbohydrazide in 350 ml of pyridine with stirring and cooling. After addition, the mixture is stirred for a further 3 hours at room temperature and subsequently mixed with 6 liters of water. The precipitate obtained is separated, dissolved and reprecipitated from methanol/water and, after drying in air is mixed with 1.7 liters of boiling ethyl acetate and after cooling, is suction filtered and dried in the air. 112 g of 1,5-bisbenzoyl-thiocarbohydrazide which melts at 177° to 179° C. with decomposition are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([NH2:25])=[S:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Br[CH2:32][C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[S:24][CH:32]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:25]=2)=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)C1=C(COCc2nc(C(=O)OCC)cs2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
2-{[4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-ethoxycarbonylthiazole was prepared by the method of Example 44 but using 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-thioacetamide and ethyl 3-bromopyruvate as starting materials.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:19])[C:12](=[O:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH3:9][O:10][C:11](=[O:19])[C:12]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:18])[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(=O)c1cccs1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
98.6 ml (0.197 mol) of a 2M solution of Cyclohexylmagnesium chloride in diethyl ether, were added to a solution of 27.97 g (0.164 mol) of 2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 370 ml of THF, at −78° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained was purified by column chromatography (silica gel) using hexane/AcOEt 90:10 as eluent. The yield was 16.2 g (39.5%) of a pure product, whose structure was confirmed by 1H-NMR.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH:18][CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:21](OC)=[O:22])=N[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:31][C:14]([N:17]2[C:21]([OH:22])=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CNNc1ccc(C(=O)NCc2ccccc2)cn1)c1ccccn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-c3ccccn3)c2O)cc1

Procedure:
Combined methyl 3-(2-(5-(benzylcarbamoyl)pyridin-2-yl)hydrazinyl)-2-(pyridin-2-yl)acrylate (110 mg, 0.273 mmol) and potassium carbonate (56.5 mg, 0.409 mmol) in ethanol (10 mL) and heated at 60° C. for 1 hour. The precipitate was filtered and washed with ethanol to give an off-white solid. This solid was then dissolved in ethyl acetate. The organic layer was washed with water, dried and concentrated to give the title compound as a yellow solid. (60 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.50 (d, J=6.06 Hz, 2H), 6.69 (ddd, J=7.07, 4.80, 1.26 Hz, 1H), 7.19-7.30 (m, 1H), 7.34 (d, J=4.55 Hz, 4H), 7.44 (ddd, J=8.21, 7.20, 2.02 Hz, 1H), 7.85 (s, 1H), 8.10-8.19 (m, 2H), 8.19-8.25 (m, 1H), 8.64 (dd, J=8.84, 0.76 Hz, 1H), 8.84 (dd, J=2.53, 0.76 Hz, 1H), 9.04 (t, J=5.81 Hz, 1H). MS m/z [M+H]+ 372.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[P:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(P(c2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 3,4,5-trimethoxybromobenzene 18 (62.3 g, 0.25 mol) in dry THF (200 ml) was added BuLi solution (169 ml, 1.6M in hexane, 0.27 mol) dropwise at −78° C. within 45 min. The resulting beige-colored suspension was stirred for an additional 1 h at −78° C. Then PPh2Cl (61 g, 0.277 mol, 49.7 ml) was added dropwise. The addition was complete within 2 h. The resulting yellow solution was allowed to warm to 0° C. within 2 h and quenched by addition of NH4Cl solution (200 ml). The organic layer was separated, washed with brine (250 ml), dried (Na2SO4), filtered, and evaporated. The solid was recrystallized from methanol to give 69.5 g(80%) of 19.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=[O:17])=[C:12]([CH3:19])[CH:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[C:4]([CH3:21])[CH:3]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN(C)C1C=CN=CC=1>[C:22]1([O:17][C:16]([C:14]2[C:13]3[C:8]([N:7]=[C:6]4[C:15]=2[C:2]([CH3:1])=[CH:3][C:4]([CH3:21])=[CH:5]4)=[CH:9][C:10]([CH3:20])=[CH:11][C:12]=3[CH3:19])=[O:18])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(C)c2c(C(=O)O)c3c(C)cc(C)cc3nc2c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C(=O)Oc3ccccc3)c3c(C)cc(C)cc3nc2c1
Yield: 55 %

Procedure:
In step 1, 1,3,6,8 tetramethylacridine-9-carboxylic acid was esterified with phenol in THF and 4-dimethylamino-pyridine [DMAP]. Phenyl-1,3,6,8-tetramethylacridine-9-carboxylate was obtained in about 55% yield after recrystallization from benzene.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N:15]=[N+:16]=[N-:17])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N:15]3[CH:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16]3)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: CCN(CC)c1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Reactant: C#Cc1ccccc1
Product: CCN(CC)c1ccc2cc(-n3cc(-c4ccccc4)nn3)c(=O)oc2c1

Procedure:
This example illustrates the fluorogenic conjugation of 7-diethylamino-3-azidocoumarin and phenylacetylene to form 7-diethylamino-3-(4-phenyl-[1,2,3]triazol-1-yl)-chromen-2-one.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:44]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)#[N:45]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:10]1[C:2]([C:49]2[CH:50]=[CH:51][C:46]([C:44]#[N:45])=[CH:47][CH:48]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[C:7](=[O:23])[C:6]2([CH2:31][C:32]1[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=1)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2(Cc1ccncc1)Cc1ccncc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 6-bromo-7-methyl-1-naphthalen-2-ylmethyl-3,3-bis-pyridin-4-ylmethyl-1,3-dihydro-indol-2-one (200 mg, 0.365 mmol) in 4 ml of toluene and 2.5 ml of EtOH was added tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) under an atmosphere of dry N2, followed by the addition of a solution of aqueous sodium carbonate (Na2CO3) (77 mg, 0.738 mmol) dissolved in 2 ml of water and 4-cyanobenzene boronic acid (101 mg, 0.686 mmol). The reaction mixture was heated to 100° C. and stirred at this temperature overnight. The reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product. It was chromatographed on silica gel eluting MeOH/NH4OH/CHCl3/(3/0.3/97) to give the titled compound of Example 10 (194 mg, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J=6.8 Hz), 1.29 (m, 2H), 1.46 (m, 2H), 2.49 (t, 2H, J=7.6 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.40 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 428.9 (M++1).