Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:3]2[C:2]([O:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:7][N:6]3[CH:8]=[N:9][N:10]=[C:5]3[C:4]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2c(Cl)nn3cnnc3c2-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CO)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1ccc(COc2nn3cnnc3c(-c3ccc(Cl)cc3)c2-c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To round bottom flask was added 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (37.6 mg, 0.10 mmol), 4-methyoxybenzyl alcohol (0.15 mmol), THF (1 ml) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) (30 mg, 0.11 mmol). The reaction was heated to 50° C. and stirred at this temperature for 40 hrs. The solvent was removed and the residue was purified using preparative HPLC to give pure product 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine as a solid. HPLC retention time (method C) 7.91 min; LCMS (M+H)=477.10.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH3:9][N:10]([CH2:12][C:13]1[S:17][C:16]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=1)[CH3:11]>C(O)C>[N+:5]([NH:4][C:3]([NH:22][CH2:21][CH2:20][S:19][CH2:18][C:16]1[S:17][C:13]([CH2:12][N:10]([CH3:9])[CH3:11])=[CH:14][CH:15]=1)=[NH:8])([O-:7])=[O:6]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CN(C)Cc1ccc(CSCCN)s1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(=N)N[N+](=O)[O-])s1
Yield: 52.2 %

Procedure:
A suspension of N-nitrocarbamimidothioic acid methyl ester (1.05 g) and 2-[[[5-(N,N-dimethylaminomethyl)2-thienyl]methyl]thio]ethanamine (1.6 g) in ethanol (10 ml) was heated at 45° for 10 min. The resultant solid was recrystallised from ethyl acetate to give the title compound as white crystals (1.15 g) m.p. 118°-118.5°. TLC silica/methanol, Rf 0.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13].[CH3:21]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:21]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COCC(=O)C(=NNc1cc(I)ccc1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cc(I)ccc2F)cc(OC)c1=O
Temperature: 0 °C
Yield: 78 %

Procedure:
A mixture of methyl 2-[(2-fluoro-5-iodophenyl)hydrazono]-4-methoxy-3-oxobutanoate (14.2 g, 35.9 mmol) in N,N-dimethylformamide dimethyl acetal (142 mL) was heated to reflux for 1.5 h and cooled to 0° C. The precipitates were collected by filtration, washed with hexane and dried to yield the title compound (11.3 g, 78% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.80 (3H, s), 3.82 (3H, s), 7.37 (1H, dd, J=10.6, 8.7 Hz), 7.90-8.01 (1H, m), 8.14 (1H, dd, J=7.2, 2.3 Hz), 8.55 (1H, s).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.O.[NH2:30][NH2:31].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:31][N:30]=2)=[CH:22][CH:23]=1
Reactant: NN
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (3.2 g, 8.5 mmol, prepared in Synthetic Example 27) in DMF (50 ml) was added hydrazine monohydrate (80%, 1.2 ml, 30 mmol, 3.5 eq.), and the mixture was then stirred at 130° C. for 2 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (3.1 g, 98%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]1[CH2:29][N:28]2[C:12]3[C:13](C[CH2:26][CH2:27]2)=[C:14]2[O:21][C:19](=[O:20])[C:18]([C:22](O)=O)=[CH:17][C:15]2=[CH:16][C:11]=3C1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:9][CH2:29][N:28]([C:12]1[CH:11]=[CH:16][C:15]2[CH:17]=[C:18]([C:22]3[NH:8][C:1]4[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:7]=3)[C:19]([O:21][C:14]=2[CH:13]=1)=[O:20])[CH2:27][CH3:26]
Reactant: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Reactant: Nc1ccccc1N
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1ccc2cc(-c3nc4ccccc4[nH]3)c(=O)oc2c1
Reaction time: 8 h

Procedure:
The diphenyl analog of coumarin 7 was prepared by the dehydration/condensation (J. B. Hendrickson, M. S. Hussoin, J. Org. Chem. 1987, 52, 4139-4140) of o-phenylenediamine with the diphenyl analog of coumarin 343. A solution of 7.9 ml of triflic anhydride in 150 ml methylene chloride was added to a solution of 26.16 g triphenylphosphine oxide in 150 ml methylene chloride at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to come to room temperature and a solution of 2.54 g o-phenylenediamine and 7 g diphenyl analog of coumarin 343 prepared according to the method of Example 2 in 80 ml methylene chloride was added dropwise. The slurry was stirred overnight. The reaction mixture was washed with 5% sodium bicarbonate, water and brine, dried of magnesium sulfate, filtered, and rotary evaporated to remove the solvent. The product was isolated by flash column chromatography in methylene chloride.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]2[N:5]=1)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[NH:30][C:31](=[O:33])[CH3:32]>>[CH3:21][S:18]([N:17]([CH2:16][C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:26][C:27]4[CH:28]=[C:29]([NH:30][C:31](=[O:33])[CH3:32])[CH:34]=[CH:35][CH:36]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:22])(=[O:20])=[O:19]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CN(Cc1cccc(-c2ccc3cnc(S(C)=O)nn23)c1)S(C)(=O)=O
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccc(CN(C)S(C)(=O)=O)c4)n3n2)c1

Procedure:
N-[3-(7-{3-[(Methanesulfonyl-methyl-amino)-methyl]-phenyl}-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-acetamide was prepared from N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-N-methyl-methanesulfonamide and 3′-aminoacetanilide in an analogous manner to Example 1049. Product isolated as a yellow foam (25 mg, 22%). LCMS (m/e) 465 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.11 (d, 1H, J=7.7 Hz), 8.07 (s, 1H), 7.80 (s, 1H), 7.53-7.45 (m, 1H), 7.43-7.34 (m, 2H), 7.30 (s, 1H), 7.28-7.21 (m, 2H), 7.09 (s, 1H), 7.00 (d, 1H, J=4.8 Hz), 6.83 (d, 1H, J=4.8 Hz), 4.38 (s, 2H), 2.86 (s, 3H), 2.79 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.ClCCCl>CC(O)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Br)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.6 %

Procedure:
Sodium triacetoxyl-borohydride (470 mg, 2.21 mmol) was added to a solution of 4-bromo-phenylamine (252 mg, 1.47 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mmol) in 10 ml of 1,2-dicloroethtane (DCE), 0.5 ml of HOAc was added. The mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by rotovap to give 656 mg of crude (4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. It was used for next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[OH-].[Na+].O>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C(N)=O)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (103 mg, 0.27 mmol) in MeOH (20 mL) was added sodium hydroxide (68 mg, 1.69 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a brown solid (57.9 mg, 58%).
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of 12 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2,1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([OH:16])=[O:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:13][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:11])=[O:12])=[CH:19][CH:18]=1)([OH:16])=[O:15]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
In a similar manner to Example 2, 2.02 g (10 mmol) of 3-nitrobenzenesulfonamide, 1.50 g (10 mmol) of 4-carboxybenzaldehyde and 20 mg of TsOH in 150 mL of toluene were heated for 5 hours to yield 3.23 g (97%) of SULF-6 as a white powder: IR (Nujol) 3200-2500 (br), 1685, 1554, 1379, 1352, 1165 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.24 (s, 1), 8.47 (s, 1), 7.9-6.9 (m, 7).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:26]=[CH:25][C:24]=1[C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[N:40][CH:39]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CC1
Product: CN1CCN(S(=O)(=O)c2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H21F4N5O2S, 495.14; m/z found, 496.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.63-8.61 (d, J=1.4, 2H), 8.40-8.37 (d, J=1.4, 1H), 8.10-8.05 (m, 1H), 7.70-7.67 (d, J=8.0, 1H), 7.67-7.63 (m, 1H), 7.46-7.30 (m, 2H), 2.86 (s, 3H), 3.83-2.53 (br m, 8H).
Reaction SMILES: C([Li])CCC.[C:6]1([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19 %

Procedure:
A solution of butyllithium (1.6 M, 1.19 mL, 1.9 mmol) was added at −78° C. to a solution of 1-phenyl-1H-indole (5a) (350 mg, 1.81 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere. After 45 minutes, a solution of ethyl glyoxylate in toluene (50%, 400 μL, 2 mmol) was added. The reaction mixture was slowly warmed to room temperature for 12 hours, quenched with water (2 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (5b) as a white solid (100 mg, 0.33 mmol, 19%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.ClCCl.CN1CCOCC1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccccc1
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a solution of 0.37 g (3 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole in 15 ml of dichloromethane 0.8 ml (7.3 mmol) of N-methylmorpholine and 0.8 ml (6.9 mmol) of benzoyl chloride were successively added at room temperature. After 16 hours under stirring the mixture was concentrated and the residue was dissolved in 15 ml of methanol. 3.5 ml of sodium hydrate 2.5 M were added dropwise and 10 ml of tetrahydrofuran were finally added in order to obtain a homogeneous solution. After 15 minutes the mixture was concentrated and poured into water. The precipitate was filtered and dried in vacuum to afford 585 mg (86% yield) the title compound.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.O1CCO[CH2:19]1>>[CH:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH2:9][N:10]2[CH2:19][C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11]2)[CH:5]=1.[ClH:1]
Reactant: C1COCO1
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
N-[(2-chlorophenyl-methyl)]-2-(2-thienyl)ethylamine HCl (28.8 g) is suspended in 75 ml of 1,3-dioxolane. Hydrochloric acid at 37% concentration (0.25 ml) is added and the temperature of the reaction mixture is brought to 80° C. for 5 hours. Thereafter the reaction is complete. The mixture is cooled to room temperature, and the compound precipitates out. To complete the precipitation and simplify filtration, 75 ml of ethyl acetate is added to the reaction mixture. The filter cake is washed with ethyl acetate (2×20 ml) and dried at 60° C. UV. Ticlopidine HCl (28.5 g, 95% yield) is obtained with m.p. 208-210° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.288 mmol), 2-chloro-5-(trifluoromethyl)pyridine (53 mg, 0.288 mmol) and potassium carbonate (80 mg, 0.576 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (85 mg, 76%) as an off white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([SH:33])[CH:28]=[C:29]([Cl:32])[C:30]=1[Cl:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][C:12]([S:33][C:27]3[CH:28]=[C:29]([Cl:32])[C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: Sc1cc(Cl)c(Cl)c(Cl)c1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Sc3cc(Cl)c(Cl)c(Cl)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 3,4,5-trichlorothiophenol [Ger. Offen. DE 2515699 19751023 (Dow Chemical Co., U.S.A.)] were reacted as starting materials at 100° C. for 72 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless amorphous solid (125.3 mg, 40.6%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 0.104 g (0.413 mmol) of 6-Chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in a mixture of tert-butanol (10 ml) and H2O (5 ml), was added 2-methyl-2-butene (2 ml) followed by a solution of NaClO2 (0.344 g, 3.80 mmol) and NaH2PO4 (0.399 g, 2.90 mmol) in water (2 ml). The mixture was stirred overnight at RT. The organic solvents were removed, and then the aqueous solution diluted with water, and washed twice with hexane. The ph of the aqueous phase was adjusted to 3 by addition of aq. HCl 1N, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 15 mg (14%) of 6-chloro-1H-indole-2,3-dicarboxylic acid 2-ethyl ester as alight yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Mg+2].[O-]CC.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:23][CH:24]([CH3:26])[CH2:25][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(C)CBr
Agent: CC[O-]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Yield: 61.9 %

Procedure:
Diethyl 3-oxopentanedioate (45.5 ml, 0.25 mol) was added to a suspension of magnesium ethoxide (prepared from magnesium turnings (9 g, 0.375 mol) and iodine (0.1 g) in dry ethanol (275 ml)), and the mixture was heated under reflux for 90 min. 1-Bromo-2-methylpropane (54 ml, 0.5 mol) was added, and the reaction was heated under reflux for 16 h. Further 1-bromo-2-methylpropane (27 ml, 0.25 mol) was added to the boiling mixture, and after 3 h the solvent was evaporated in vacuo. The residue was partitioned between 2N hydrochloric acid and ether. After extracting the aqueous phase with ether, the combined organics were washed successively with water, 5% sodium bicarbonate, water and brine, then were dried (Na2SO4) and evaporated in vacuo. The residue was distilled to give the title compound as a colourless oil (40 g, 62%), bp 118°-120° C. (1mmHg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16]3[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C.O1CCOCC1>[NH2:22][C:21]1[C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1OC1CCCC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(Nc2ncccc2N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-[(3-cyclopentyloxy-4-methoxyphenyl)-amino]-3-nitropyridine (1.30 g) and 10% palladium on carbon (0.3 g) in ethanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]pyridine (992 mg).