Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CNCCO1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCOC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
1.28 g (4.63 mmole) of 2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 30 ml of methylene chloride, and 2.66 g (26.3 mmole) of triethylamine, 1.28 g (5.55 mmole) of 3,4,5-trimethoxybenzoyl chloride and 5 mg of 4-dimethylaminopyridine were added to the resulting solution. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the reaction solution was poured into an aqueous solution of sodium hydrogencarbonate and extracted with methylene chloride. The extract was then washed with a saturated aqueous solution of sodium chloride. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of methylene chloride and acetone ranging from 4:1 to 7:3 by volume as the eluent, to obtain 1.72 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 65.7 %

Procedure:
25 g (0.13 mol) of 2,4-dichloro-1-nitrobenzene, 19.5 g (0.26 mol) of glycine and 18 g (0.13 mol) of potassium carbonate were heated in 200 ml of dimethylformamide at 120° C. for 3 h. The mixture was then poured into ice-water, acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: toluene/acetone/acetic acid=20:10:1) to yield 19.7 g (66%) of the product. Melting point 147°-148° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:35])[CH:7]=[C:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[N:26]([CH3:33])[CH:25]=2)=[CH:16]3)=[O:12])[CH:9]=1)=[O:4].[OH-].[Na+]>O.CO>[OH:31][C:29]([C:27]1[N:26]([CH3:33])[CH:25]=[C:24]([NH:23][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:11]([NH:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:35])[CH:7]=2)=[O:12])=[CH:21][CH:20]=3)=[O:34])[CH:28]=1)=[O:30]
Reactant: COC(=O)c1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)OC)n(C)c4)cc3c2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)O)n(C)c4)cc3c2)cc1C(=O)O
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A solution of 4-({1-[2-(5-methoxycarbonyl-1methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 (1.04 g, 2.18 mmole) and NaOH (10 mmole) in a mixture of water/MeOH (1/4) (25 ml) was stirred at 50C. for 6 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (50 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give 0.85 g (87%) of 4-({1-[2-(5-hydroxycarbonyl-1-methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2-carboxylic acid 9 as white crystalline material. MS: 448.08 (M−H). 1-NMR (DMSO-d6): 11.96 (s, 1H, H-1, indole); 10.45&10.25 (s&s, 1H&1H, —C(═O)NH); 8.30 (m, 1H, H-6, indole); 7.48 (m, 3H with *, H-7, indole); 7.49&7.46 (d&d, *, H-3 or H-5, Py1&Py2); 7.39 (s, 1H, H-3, indole); 6.91 (m, 2H, H-3 or H-5, Py1&Py2); 3.84&3.83 (s&s, 6H, NCH3, Py1&Py2).
Reaction SMILES: [CH:1]1([N:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11](Br)=[C:10]([CH3:15])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:35])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>N1C(C)=CC(C)=CC=1C>[CH:17]1([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([O:35][C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)=[C:10]([CH3:15])[CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2C)cc(OC)c1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using 4-bromo-3-methyl benzoic acid N-cyclopentyl-N-cyclohexyl amide (983 mg, 2.7 mmol), 3,4,5-trimethoxy phenol (983 mg, 2.7 mmol) and cuprous oxide (200 mg, 1.3 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 181-182° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH:10]([CH3:11])[C:9](=[O:12])[CH:8]=[CH:7][CH2:6]1.[H][H]>CCOC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[CH:10]1[CH3:11]
Reactant: CC1C(=O)C=CC[C@@H]1CCCO
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC1C(=O)CCC[C@@H]1CCCO
Yield: 100.2 %

Procedure:
A solution of 21.8 g (0.129 mole) of the crude (5S)-5-(3-hydroxypropyl)-6-methyl-2-cyclohexene-1-one in 200 ml of EtOAc was stirred with 1.0 g 10% Pd(C) under 1 atmosphere pressure of hydrogen until a total of 2600 ml of hydrogen was consumed. The reaction mixture was then filtered through a pad of celite which was washed further with EtOAc. The combined filtrates were concentrated to give 22.0 g of the crude ketone which was chromatographed on a silica gel column (4:1, hexane/EtOAc) to give 13.5 g (50% from s-carvone) of the pure (3R)-3-(3-hydroxypropyl)-2-methycyclohexanone. B.P. 110° C./0.15 mmHg. IR (CHCl3): 1702, 3475, 3625 cm-1.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C.C(O)C.Cl>C(O)C>[NH2:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)CCCCc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCCc1ccc2c(c1)C[C@@H](N)CC2
Yield: 101 %

Procedure:
Ethyl (S)-5-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yl]valerate (687 mg) was dissolved in ethanol (10 ml), and 3 M hydrogen chloride ethanol solution (3 ml) was added to the solution at room temperature with stirring. After reaction for 15 hours, the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution (10 ml) and dichloromethane (5 ml) were added to the residue, and the resulting mixture was stirred for an hour at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave ethyl (S)-5-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)valerate (509 mg) as an oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[S:19])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.CS(O[CH2:32][CH3:33])(=O)=O.C([O-])(=O)C.[NH4+].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)/C=C\C(O)=O>CO.C(OCC)(=O)C.C(OCC)C.O.C(O)C>[C:1]1([CH2:7][N:8]([CH3:21])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([S:19][CH2:32][CH3:33])=[NH:20])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CCc1ccc(NC(N)=S)cc1)Cc1ccccc1
Reactant: CCOS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCSC(=N)Nc1ccc(CCN(C)Cc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
1-(4-(2-((Phenylmethyl)(methyl)amino)ethyl)phenyl)-2-thiourea (step (f), 0.30 g) was suspended in 200 ethanol (2.5 ml), and the mixture was treated with methanesulfonic acid (0.065 ml) and then ethyl methanesulfonate (0.12 ml). After 3 hours at 100° C., TLC on C18 silica with 80% methanol/20% water with 0.8% ammonium acetate showed incomplete conversion to product. At this point additional ethyl methanesulfonate (0.20 g) was added and the mixture refluxed for one hour. After stirring overnight, the crude reaction product was treated with ethyl acetate (50 ml) and water (50 ml). The aqueous layer was treated with sodium carbonate (0.25 g) and extracted with diethyl ether (20 ml). The remaining aqueous layer was treated with sodium bicarbonate (1 g) and extracted with of diethyl ether (20 ml). The ether layers were identical by TLC and were combined, dried with sodium sulfate and evaporated to yield the free base which was then treated with maleic acid (0.24 g) in methanol (1 ml), then diluted with ethyl acetate (4 ml) followed by diethyl ether (25 ml), giving an oil. The solvents were decanted, and the resulting solids were dissolved in hot isopropanol (20 ml) and cooled to -20° C. The resulting solids were collected and air dried to provide N-(4-(2-((phenylmethyl)(methyl)amino)ethyl)phenyl) carbamimidothioic acid, ethyl ester, 0.34 g, m.p. 136°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:20]=1.Cl>ClC(Cl)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:29]([C:19]2[CH:20]=[C:21]([S:25]([Cl:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)(=[O:31])=[O:30])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
8.78 g (30 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 88 ml of dichloroethane with exclusion of moisture, 5.55 g (70 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 9.9 g (36 mmol) of 1,3-benzenedisulfonic acid dichloride in 50 ml of dichloroethane is instilled, it is stirred for 30 more minutes at 0° C. and for 5 hours more at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane 1:1. The fractions of the corresponding polarity, concentrated by evaporation, yield 9.7 g (23.22 mmol)=77.4% of the theoretical yield is obtained of a partially crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(NC=NCCCC)CCC.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: CCCCN=CNCCCC
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 2.3 g of N,N'-dibutylformamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 97% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[N:18]1([S:15]([C:13]2[CH:12]=[CH:11][C:8]3[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=3[CH:14]=2)(=[O:17])=[O:16])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(c1ccc2c(c1)CCNCC2)N1CCOCC1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A solution of 3-acetyl-7-(morpholin-4-yl)sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g, 8.9 mmol) in 5 M hydrochloric acid was heated at reflux for 18 h. The reaction mixture was then cooled to room temperature, basified to pH=12 with potassium carbonate and the solvent evaporated in vacuo. The solid residue was then extracted with ethyl acetate (5×100 ml) and the combined organics dried (Na2SO4). The solvent was then evaporated in vacuo to give the title compound (1.49 g, 57%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][Si](CC)(CC)CC)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: CC[Si](C#Cc1cncc(Cl)c1)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cncc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
3-Chloro-5-[(triethylsilyl)ethynyl]pyridine (1.4 g, 6.7 mmol) was dissolved in methanol (15 ml) and cooled to 0° C., to the resulting solution was added potassium carbonate (93 mg, 0.67 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 0.5 h at which time thin layer chromatography (TLC) and GC/MS analysis indicated that the reaction was complete. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (50 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-chloro-5-ethynylpyridine (822 mg, 90% yield) which was pure by GC/MS analysis. MS (EI ionization) 137 (35Cl M+), 139 (37Cl M+). This material was carried on to the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[C:5]=12.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:11][C:10]([C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1cccn2ccnc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccn2ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of imidazo[1,2-a]pyridine-8-carboxylic acid (3.8 g, 23 mmol) in methanol (100 mL) is added thionylchloride (8.36 g, 70.3 mmol) and the mixture is warmed at reflux. After 8 hours, the reaction mixture is cooled to room temperature and quenched with saturated aqueous NaHCO3, and extracted with EtOAc (3×250 mL). The combined organic layers are washed with water, brine, dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 3% MeOH in CH2Cl2 to afford imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester. Mp: 71-73° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:35])[F:37])=[CH:31][CH:32]=4)[N:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)Oc1ccc(-c2cccc(CCl)n2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 2-Chloromethyl-6-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diethylether. The residue was dried at 40° C. to give 15 mg (18%) of the title compound as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:10])([CH3:11])[CH3:9]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Under the protection by nitrogen, ortho-methylphenylethanone (134 g, 1.0 mol) is dissolved in 1000 ml of tetrahydrofuran and then cooled to −5° C., into which 2 M methylmagnesium bromide in tetrahydrofuran (550 ml) is slowly added dropwise at below 0° C. After the addition, the reactant solution is stirred at room temperature for 3 hours under the detection of TLC. When the reaction is complete, 200 ml of saturated NH4Cl solution is slowly added dropwise into the reactant solution and stirred until no bubbling from the solution. The resulted solution is then extracted by dichloromethane (500 ml×3), the extracts are combined, dried by anhydrous sodium sulfate, absorbed by activated carbon, filtered, and then the solvent is distilled out using rotary evaporator to obtain 132 g of 2-ortho-methylphenyl-2-propanol as a light yellow sticky liquid, with a yield of 88%.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CS(O[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH:27]=[CH2:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH:27]=[CH2:28]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: C=CCC1CCCCC1OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCC1CCCCC1Nc1ccc(CCC(=O)OCC)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 1-methanesulfonyloxy-2-allylcyclohexane (prepared by the method of Example 189), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80 for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][C:12]=2[N+:24]([O-])=O)=[O:10])=[N:6][CH:7]=1>O1CCCC1.[Ni]>[NH2:24][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
t-Butyl 4-{[(5-chloropyridin-2-yl)amino]-carbonyl}-3-nitrobenzoate (3.2 g) obtained in Example 2(1) is dissolved in tetrahydrofuran (50 ml) and thereto is added Raney nickel, and the mixture is stirred at room temperature under hydrogen pressure (3 atm.) overnight. The insoluble materials are removed by filtration on Celite and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=20/1) to give t-butyl 3-amino-4-{[(5-chloropyridin-2-yl)amino]carbonyl}benzoate (2.3 g). APCI-MS M/Z: 348[M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:10][CH:11]=O>C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1cnc2nccn2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 mmol of 5-bromo-pyrimidin-2-ylamine are dissolved in 200 ml of saturated aqueous sodium hydrogencarbonate solution. 55 mmol of chloroacetaldehyde are added to the reaction mixture and the mixture is stirred for 24 hours at 25° C. The mixture is extracted with ethyl acetate (3×300 ml) and the combined extracts are dried over sodium sulphate and evaporated under reduced pressure. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23].Cl>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A total of 11.5 g of methyl 4-fluoro-3-(3-fluorobenzoyl)benzoate was dissolved in 40 ml of ethanol, and the reaction mixture was treated with 2.4 ml of hydrazine monohydrate with stirring at room temperature for 12 hours. The reaction mixture was treated with 2 N hydrochloric acid to be acidic and was extracted with two portions of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from hexane-diisopropyl ether, to give 7.0 g of title compound as colorless crystals.