Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[NH2:11])=[O:5])C.C(O)(=O)C.[CH:22](N)=[NH:23]>CCO>[CH2:15]([O:14][C:12]([C:9]1[C:10]2[N:11]=[CH:22][N:23]=[C:4]([OH:5])[C:6]=2[NH:7][C:8]=1[CH3:17])=[O:13])[CH3:16]
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c2c(O)ncnc12

Procedure:
A reaction flask equipped with a mechanical stirrer, a reflux condenser and a nitrogen bubbler is charged with EtOH (5000 mL), 3-amino-5-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester from example A2 (565.57 g; 2.50 mol) and formamidine acetate (1041.10 g; 10.00 mol). The well-stirred reaction mixture is heated to gentle reflux for five days under an atmosphere of nitrogen.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 1)(2.28 g, 8.05 mmol) and 6-chloronicotinonitrile (2.231 g, 16.10 mmol) was added NMP (20 mL) and the mixture treated with DIPEA (4.22 mL, 24.16 mmol). The mixture was split between 2 flasks and each flask was flushed with nitrogen, sealed and stirred under microwave irradiation at 200° C. for 2 h. The reaction mixtures were combined and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×4) and the combined organic layers were washed with water (×3), then brine and were dried (MgSO4) filtered and concentrated in vacuo. The brown solid residue was purified by chromatography (EtOAc in Hexanes gradient) to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (1.940 g, 5.04 mmol, 62.5% yield) as a pale yellow foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=386 (1 Br).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O=[C:7]([NH:12][CH:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][CH2:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:8]([O:10][CH3:11])=[O:9]>C(Cl)CCl>[F:21][C:16]([F:22])([C:17]([F:20])([F:19])[F:18])[CH2:15][CH2:14][C:13]1[N:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: COC(=O)C(=O)NC(CCC(F)(F)C(F)(F)F)c1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1nc(CCC(F)(F)C(F)(F)F)c2ccccn12
Temperature: 120 °C

Procedure:
Phosphoryl chloride (1.428 mL, 15.36 mmol) was added to a stirred solution of the intermediate from Step D (0.6534 g, 1.920 mmol) in dry ClCH2CH2Cl (14.44 mL). The resulting solution was heated at 120° C. overnight. Another 8 eq. POCl3 was added and the reaction was heated at 120° C. for 2 days. The reaction was cooled to room temperature and concentrated in vacuo. The reaction was diluted with water and EtOAc and basified by the careful addition of saturated aq. NaHCO3 until not further effervescence was observed. The layers were separated and the aqueous layer was further extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by silica gel chromatography using a hexanes/EtOAc gradient to afford the desired product, as a colorless solid. 1H NMR (500 MHz, CHCl3-d) δ 9.31 (d, J=7.2 Hz, 1H); 7.59 (d, J=9.1 Hz, 1H); 7.08 (dd, J=9.0, 6.6 Hz, 1H); 6.96-6.90 (m, 1H); 4.03 (s, 3H); 3.25-3.19 (m, 2H); 2.66-2.52 (m, 2H). m/z=323.0 (M+H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=1)(=O)C.C[O-].[Na+]>CO>[C:15]([C:12]1[O:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:14][CH:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCCCCCc1ccc(C(C)=O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc(CCCCCO)o1
Yield: 74.7 %

Procedure:
5-(5-Acetyl-2-furanyl)pentanol acetate (60.6 g) was hydrolyzed with 3 g of sodium methoxide in 900 ml of absolute methanol and the product isolated to give 37.3 g of 5-(5-acetyl-2-furanyl)pentanol, b.p. 132°-135° C. (0.1 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(OC([N:50]1[CH2:54][CH2:53][C@H:52]([C@H:55](O)[CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:51]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:58]([O:57][CH2:56][C@@H:55]([C@H:52]1[CH2:53][CH2:54][NH:50][CH2:51]1)[O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Reactant: Cc1cc(Cl)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1O[C@@H](COCc1ccccc1)[C@H]1CCNC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-methylphenol (14.1 mg, 98.9 μmol) was combined with PPh3 (26.0 mg, 98.9 μmol) dissolved in toluene (87.8 μL), and the mixture heated at 100° C. DIAD (19.5 μL, 98.9 μmol) was combined with (S)-3-((S)-2-benzyloxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (19.1 mg, 59.3 mmol) dissolved in toluene (58.0 μL), and slowly added to the heated mixture and stirred for two hours. The mixture was cooled to room temperature and concentrated. The residue was treated with 1.25M HCl in EtOH (474.6 μL) overnight at room temperature. The mixture was concentrated, the residue was redissolved in a mixture of MeCN (0.4 mL), AcOH (0.6 mL) and water (0.6 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (7.8 mg, 99% purity). MS m/z: [M+H]+ calcd for C20H24ClNO2, 346.15. found 346.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH:12]=1)(=O)=O.[CH2:22]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(O)C.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>[CH2:22]([N:29]1[CH:33]=[C:32]([C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][CH:12]=2)[CH:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC=C(c2cnn(Cc3ccccc3)c2)C1
Yield: 97.5 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (5.0 g, 15.11 mmol, 1.00 equiv) in toluene (100 mL), a solution of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.29 g, 15.11 mmol, 1.00 equiv) in ethanol (100 mL), triethylamine (4.58 g, 45.35 mmol, 3.00 equiv), Pd(PPh3)4 (345 mg, 0.30 mmol, 0.01 equiv) and water (30 mL). The resulting mixture was heated to reflux for 3 hours. Upon completion, the mixture was diluted with water (100 mL). Then, it was extracted with ethyl acetate (3×200 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:5) affording tert-butyl 3-(1-benzyl-1H-pyrazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as yellow oil (5.0 g, 98%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:17]Cl.CO.C[Si](C=[N+]=[N-])(C)C>O.C(O)=O>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(F)c(F)cc1NC1CC1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(F)c(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5a) (6.0 g, 28.1 mmol), dichloromethane (100 mL), and methanol (20 mL) is added (trimethylsilyl)diazomethane (2.9 M solution in hexane) dropwise until the evolution of gas stops. The solution is stirred at room temperature for 0.5 hour and 88% formic acid is added dropwise until the evolution of gas again stops. Water is added, and the solution is extracted with dichloromethane, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue is purified by silica gel column chromatography using hexane/EtOAc (9:1) as the eluent to afford a 5.4 g of the title compound as a clear oil. MS CI: m/z 228 (MH+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(O)CCOc1cccc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cccc(OCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethoxy)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethoxy)-2-pyridyl]thiazole.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)=[O:5])C.[CH2:22]([NH2:24])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)=[O:5])[CH3:23]
Reactant: CCOC(=O)c1cc(-c2cccnc2)cc2nc(N)nn12
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(-c2cccnc2)cc2nc(N)nn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the product of Step 1 (0.69 g, 2.45 mmol) in 2 M solution of ethylamine in THF (15 mL) was allowed to stir at room temperature for 2 days. The solid precipitate was filtered to give 2-amino-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-carboxylic acid ethyl amide as a solid. MS m/z 283 (M+H+).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][S:20][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: CN(C)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCSc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.3 %

Procedure:
A suspension of tert-butyl 4-fluorobenzoate (300 mg), 2-(dimethylamino)-ethanethiol hydrochloride (420 mg), and potassium carbonate (620 mg) in dimethylsulfoxide (3.0 mL) is stirred at 80° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is concentrated in vacuo and to the residue is added 4N HCl-dioxane (1.5 mL). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ether and the precipitated crystals are collected by filtration to give 4-[2-(dimethylamino)ethylthio]-benzoic acid (380 mg, yield; 99%) as colorless crystals. MS (APCI) m/z; 226 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[CH3:12][C:13](=[CH:15][CH2:16]Br)[CH3:14]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cccc(SCC=C(C)C)c1
Yield: 90.4 %

Procedure:
50.45 g (360.0 mmol) of 3-methoxythiophenol, 360 ml of acetone and 14.40 g (360.0 mmol) of sodium hydroxide pellets are introduced into a one liter round-bottomed flask under a nitrogen atmosphere and the mixture is heated at reflux for three hours. A solution composed of 53.65 g (360.0 mmol) of 2-methyl-4-bromo-2-butene and of 60 ml of acetone is added dropwise. Reflux is maintained for sixteen hours and the reaction mixture is evaporated to dryness. Water is added, extraction is carried out with ethyl acetate, the organic phase is washed with water and then using a saturated sodium chloride solution, dried over magnesium sulphate and filtered, and the solvents are evaporated. The residue obtained is distilled under reduced pressure (5×10-2 bar/113° C.) to produce 67.81 g (90%) of the expected compound in the form of a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NCCc3ccc(Cl)cc3)cc1)OCCC2C(=O)O
Reaction time: 3 h
Yield: 21.6 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (100 mg, 0.204 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (0.204 mL, 1.02 mmol) and 500 μL of water and methanol. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using the Horizon with a 25 cartridge and running a gradient 0.5% methanol/0.5% acetic acid/CH2Cl2 to 10% methanol/0.5% acetic acid/CH2Cl2 to yield the title compound (21 mg, 21.6% yield) as a white solid. MS (ESI)=476.9 (M+1).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:27]4[CH2:29][CH2:28]4)[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.CO>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:27]4[CH2:28][CH2:29]4)[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C1CC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C1CC1)c1ccccc1
Yield: 31 %

Procedure:
Prepared analogously to Example 25d from 1-Cyclopropyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 31% of theory, C30H33N6O3 (524.6) Rf value: 0.40 (silica gel; dichloromethane/methanol=5:1) ##EQU98##
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[N:3]=1>C1COCC1.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:4]2[N:5]=[C:6]([Cl:13])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([Cl:1])[N:3]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.00 g, 5.62 mmol) in anhydrous THF (50 mL) was treated with Pd/C (10% Pd, 0.200 g) and the resulting black suspension was stirred under an atmosphere of hydrogen at room temperature. After 16 hours, the reaction mixture was filtered over Celite and the residue rinsed with copious amounts of MeOH. The filtrate was concentrated in vacuo to give the crude product as a dark yellow oil which was chromatographed (silica gel, 40% EtOAc in n-hexane) to give methyl [2-(4-aminobenzyl)-4,6-dichloropyrimidin-5-yl]acetate (1.32 g, 72% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[S:26]>C1(C)C=CC=CC=1>[CH3:23][NH:24][C:25]([N:20]1[CH2:21][CH2:22][CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:18][CH2:19]1)=[S:26]
Reactant: CN=C=S
Reactant: Fc1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)N1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 55.1 %

Procedure:
A stirred mixture of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 102 (30 g, 0.094 moles) and 25% H2SO4 (225 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 21 g (76%) of 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.0135 moles) in toluene (70 ml) was added dropwise methyl isothiocyanate (1.5 ml, 0.022 moles). The mixture was stirred for 23 hours at ambient temperature during which time the product precipitated from the solution. The product was collected and recrystallized twice from isopropyl alcohol to yield 2.74 g (55%) of N-methyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbothioamide, m.p. 179°-181° C.
Reaction SMILES: [C:1]1([O:7]C)C=CC=CC=1.[C:9]([NH:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)(=[O:11])[CH3:10]>>[OH:19][C:15]1[CH:14]=[C:13]([NH:12][C:9](=[O:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[CH:1]=[O:7]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: COc1ccccc1
Product: CC(=O)Nc1ccc(C=O)c(O)c1

Procedure:
By operating according to Example 13, but using anisole as the solvent and a temperature of 100° C., and starting from 15.1 g of 3-acetylaminophenol, 9.0 g of a product (yield on the theoretical value=50%) having a melting point at 185°-186° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[SH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].N12CCCN=C1CCCCC2>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCS
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
tert-Butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)carbamate (Example 44A) is synthesized in analogy to the preparation of Example 42A from 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) (500 mg, 1.7 mmol), tert-butyl (2-mercaptoethyl)carbamate (445 mg, 2.5 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (382 mg, 2.5 mmol). The crude product is purified by flash chromatography (eluent: cyclohexane/ethyl acetate), and 422 mg (93% of theory) of the product are obtained after evaporation of the solvent.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Yield: 431.2 %

Procedure:
A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)-carbamate (550 mg, 0.230 mmol), K2CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg). 1H NMR δ 8.15 (s, 1 H), 7.47-7.44 (m, 2 H), 7.22 (t, 1 H, J=7.8 Hz), 6.94 (d, 1 H, J=7.8 Hz), 5.53 (b, 1 H), 3.23 (b, 6 H), 2.80-1.60 (m, 9 H), 2.20 (s, 3 H), 1.45 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)(=[O:11])=[O:10])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)cc(F)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of 3,5-difluoro-benzenesulfonyl chloride (252 mg, 1.19 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (300 mg, 1.19 mmol) in CH2Cl2 (7 mL) was added anhydrous pyridine (144 μL, 1.77 mmol, 1.50 equiv.) and the vial capped and shaken for 72 h. The reaction solution was transferred to a separatory funnel with CH2Cl2 (100 mL), washed with 1M citric acid solution (100 mL), water (50 mL×4), brine (100 mL), dried (MgSO4), filtered and evaporated to give a white solid (300 mg, 59%). Mass Spectrum (−ESI): 427.8 [M−H]−
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[CH:6][C:5]=12.N>CO.[Ni]>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]=[CH:6][C:5]=12
Reactant: N#Cc1cn2ccnc2cn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cn2ccnc2cn1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of imidazo[1,2-a]pyrazine-6-carbonitrile (5-1) (180 mg, 1.25 mmol) in methanol (15 mL) were added Raney nickel (slurry in water, 150 mg) and 1 N ammonia. The reaction mixture was stirred under H2 (1 atm) for 2 h. The mixture was filtered, and the filtrate was concentrated to afford the title compound (160 mg). MS (m/z): 149.1 (M+H)+