Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])=[O:10]
Reactant: NCc1ccccc1F
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1F)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
In a flask were placed 4 grams (g) (0.01326 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride, dissolved in methylene chloride. There was then added 1.7 g (0.01326 mole) of 2-fluorobenzylamine, very slowly, with vigorous stirring. After about 15 minutes, 1.34 g (0.01326 mole) of triethylamine was added dropwise. The reaction mixture was stirred for a short time, then heated intensely for about 5 minutes and allowed to return to room temperature. After approximately 1/2 hour, 5% aqueous sodium carbonate solution was added with stirring continued. The aqueous and organic phases were separated; the aqueous phase was decanted off and the organic phase washed twice with 5% sodium carbonate solution and twice with water. The organic phase was then dried over sodium sulfate; solvent was stripped off, and an oil-like mixture was recovered, which crystallized in a short time. The solid was then washed with pentane to remove any remaining amine. There was obtained 3.5 g (67% of theoretical yield) which was identified as the desired compounds by infrared, nuclear magnetic resonance, and mass spectroscopic analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][C:26]([NH:1][C:2]2[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)c1ncccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ncccc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry CH2Cl2 (20 mL) was added to methyl 3-aminopicolinate (116) (0.421 g, 2.77 mmol). The solution was purged with nitrogen. Triethyl amine (1.16 mL, d=0.726, 8.31 mmol) was added to the solution via syringe. Phenylacetyl chloride (117) (0.805 mL, d=1.169, 6.09 mmol) was added to the solution via syringe. The mixture was stirred overnight at room temperature under nitrogen. The mixture was then stirred at 40° C. for 6 h. More triethyl amine (0.50 mL, 3.6 mmol) was added and, an hour later, more phenylacetyl chloride (0.400 mL, 3.02 mmol) was added. The mixture was stirred an additional hour and allowed to cool to room temperature. The reaction was quenched with water (20 mL), and the aqueous layer removed. The organic layer washed with water (3×15 mL), and dried with MgSO4. Silica gel was added and the slurry rota-evaporated to dryness. The resulting silica was chromatographed on silica (40 g, Davisil, grade 643, mesh 200-450) and eluded with EtOAc-hexanes (2:1, 400 mL). The appropriate fractions were collected (Rf =0.35). The solvent was rota-evaporated to yield the title compound (118) as a yellow oil, which, upon drying, precipitated out as a yellow solid (0.4463 g, 59.6%); Rf =0.35. 1H NMR (CDCl3) δ3.78 (s, 2, benzyllic), 3.97 (s, 3, CH3O--), 7.38 (m, 6, phenyl & H-5), 8.39, (dd, J1 =0.6, J2 =3.9, 1, H-4), 9.10 (dd, J1 =8.4, J2 =8.3, 1, H-6), 10.96 (s, 1, NH); MS (m./z) 270 (M+, 35), 211 (35), 179 (85), 153 (40), 147 (65), 119 (40), 94, (40), 91 (100).
Reaction SMILES: [H-].[Na+].[CH:3](/[C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CN(C)C=O>[CH:3]([C:11]1[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C(=C/c1ccc[nH]1)\c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cccc1C=Cc1ccccc1
Yield: 34.5 %

Procedure:
Sodium hydride (0.3 g, 0.0063 mol) was washed with petrol 60°-80° and suspended in dimethylformamide (DMF, 25 ml). The (E)-2-styrylpyrrole (1.0 g, 0.006 mol) in DMF (10 ml) was added dropwise at room temperature. After stirring for 11/2 hours, methyl bromoacetate (0.56 ml, 0.006 mol) in DMF (5 ml) was added dropwise. After 16 hours it was poured into water (200 ml) and extracted with ether (3×100 ml). The extracts were washed with brine dried and evaporated under reduced pressure to give a brown oil. Purification by column chromatography using silica gel with ethyl acetate: petrol 60°-80°, (1:1) as the eluent gave methyl (2-styrylpyrrol-1-yl)acetate (0.5 g, 30% yield) as a buff amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:25]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.10 g (0.60 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one in 1.5 mL DMF were combined with 0.10 g (0.70 mmol) potassium carbonate and stirred for 15 min at RT. Then 0.10 g (0.60 mmol) 4,6-dichloropyrimidine were added to the reaction mixture and stirred overnight at RT. Then water was added and the precipitate formed was suction filtered, washed and dried i. vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([C:7]([O:22][CH2:23][C@:24]23[C@H:30]([OH:31])[C@H:27]([O:28][CH2:29]2)[C@H:26]([N:32]2[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]2=[O:34])[O:25]3)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:47](Cl)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CCOC(C)=O>[Si:47]([O:31][C@@H:30]1[C@@H:27]2[O:28][CH2:29][C@@:24]1([CH2:23][O:22][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:6]1[CH:40]=[CH:41][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[O:25][C@H:26]2[N:32]1[CH:39]=[CH:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@]23CO[C@H]([C@H](n4ccc(=O)[nH]c4=O)O2)[C@H]3O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 94 %

Procedure:
A solution of compound 112 (1.5 g) in anhydrous DMF (10 mL) was stirred with imidazole (0.913 g), trethylamine (375 μL) and t-butyldimethylsilylchloride (0.81 g) for 15 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with aqueous sodium bicarbonate solution (2×20 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed and the product purified on silica gel using 10% acetone in CH2Cl2. The appropriate fractions were concentrated and dried to give Compound 114 in 94% yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CS(O[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:7][C:2]1[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOS(C)(=O)=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCCNc1ccccc1N
Yield: 56 %

Procedure:
To a solution of phenylenediamine (10.8 g) and 4-methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g), and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[CH3:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: Cc1ccc(C)c(B(O)O)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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 37 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dimethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.04 g of the title compound. Yield 37% ES MS (+) m/z 371.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][CH3:2])=[C:10]([OH:16])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Br)cc1O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC=Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (8.44 g, 22 mmol, 2.2 eq.) in toluene (60 mL), a solution of potassium tert-butoxide (2.60 g, 22 mmol, 2.2 eq.) in THF (15 mL) was added dropwise. The resulting red mixture was stirred at r.t. for 4 hours. The mixture was then cooled to −78° C. and a solution of 4-bromo-2-hydroxybenzaldehyde (2.12 mg, 10 mmol, 1.0 eq.) in toluene (10 mL) was added dropwise. The resulting solution was allowed to slowly warm to r.t. and further stirred at r.t. for 20 hours. The reaction was quenched with sat. aq. NH4Cl soln. (30 mL). The mixture was diluted with water (30 mL). The layers were separated and the aq. phase was extracted with Et2O (3×30 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane/AcOEt 8:2) to yield 5-bromo-2-(propenyl)-phenol as a yellow oil as an unseparable mixture of E- and Z-isomer (ca. 85:15).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[H-].[Na+].C(O)(=O)C[C:28](CC(O)=O)(C(O)=O)[OH:29]>CN(C)C=O>[C:1]([O:5][C:6]([C@@:8]1([CH2:28][OH:29])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.5 h

Procedure:
5-Oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4 g, 13.82 mol) was dissolved in N,N-dimethylformamide (40 mL), and paraformaldehyde (0.83 g, 27.65 mmol) was suspended in the solution. Sodium hydride (0.60 g, 13.82 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction solution was poured into a 10% citric acid solution (150 mL) at 0° C. The mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (30% ethyl acetate/hexane→80% ethyl acetate/hexane) to give 1.03 g of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1])(=[O:10])[CH3:9]
Reactant: Cc1c[nH]c(C)n1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)n1cc(C)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 9.6 g (0.10 M) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene was stirred at room temperature and 3.6 ml (0.05 M) of acetyl chloride was added via syringe over 1 minute. The mixture was stirred at room temperature for 2 hours, then the mixture was filtered to remove insoluble solids, and the filtrate concentrated leaving 6.9 g (100%) of 1-acetyl-2,4-dimethylimidazole as a white crystalline solid: nmr (CDC3) (δ): 7.00 (s, 1H); 2.68 (s, 3H); 2.57 (s, 3H); 2.21 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].O.Cl>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][CH:7]=3)[N:17]=2)[CH:19]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 8 (19.6 g, 59.6 mmole) and 2N-sodium hydroxide (190 ml) were added to a reaction vessel under the solvent of water (190 ml) and ethanol (190 ml), mixed under reflux and cooled to RT, and pH thereof was adjusted to 1˜2 with hydrochloride solution. The mixture was mixed for 1 hr, and filtered to give the titled compound as yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:2]([CH3:1])=[O:3])=[CH:9][CH:8]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(Cl)c5)o4)cc23)cc1
Yield: 84 %

Procedure:
In the same manner as in Example 7 and using 5-[3-[4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-chlorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[C:10]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:24])[CH3:23])[CH:17]=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]([CH:17]([OH:18])[C:1]#[CH:2])[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:23])[CH3:24])([CH3:13])([CH3:11])[CH3:12]
Reactant: C#C[Mg]Br
Reactant: CN(C)c1c(Cl)cc(C=O)cc1C(C)(C)C
Solvent: C1CCOC1
Product: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Yield: 48.9 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 13 ml (6.5 mmol) of 0.5M ethynylmagnesium bromide/THF with 1.2 g (5 mmol) of 3-tert-butyl-5-chloro-4-dimethylaminobenzaldehyde. 650 mg of 1-(3-tert-butyl-5-chloro-4-dimethylamino-phenyl)prop-2-yn-1-ol are obtained in the form of a yellow solid (yield=49%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:31][C:30]([C:32]#[N:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:31][C:30]([C:32]#[N:33])=[CH:29][CH:28]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: N#Cc1ccc(Br)s1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C#N)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (25 mg, 38%), MS (ISP) m/z=326.5 [(M+H)+], mp 249° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 5-bromothiophene-2-carbonitrile (56.4 mg, 0.3 mmol).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].P(Cl)(Cl)(Cl)=O.[Cl:14][CH2:15][C:16](Cl)=[O:17]>O>[Cl:14][CH2:15][C:16]([C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(CCl)c1ccc(O)c(O)c1
Temperature: 125 °C
Yield: 65 %

Procedure:
Similar to the procedures of R. W. Schayer (J. Am. Chem. Soc. 74, 2441 [1952]) and N. Levin et al. (J. Org. Chem. 7, 408-415 [1942]), but without an additional solvent, a mixture of 100 g catechol, 750 g (450 ml) of phosphorus oxychloride and 206 g (145 ml) of chloracetyl chloride was stirred at reflux temperature (ca. 125° C.) in an argon atmosphere for 4.5 hours. Then most of the volatiles were distilled off at 80° C. (bath temperature) and, finally, under reduced pressure. To the nearly intractable dark mass were added at ca 80° C. 200 ml of water upon which the mixture became stirabel again. 600 ml of cold (0° C.) water were added in portions to control the exothermic reaction. When all of the water was added and the exothermic reaction had ceased the mixture was stirred for 2 hours under reflux. Upon stirring over night without further heating 125 g of crude product precipitated as dark brown crystals with a purity of about 90% (yield ca. 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17](O)=O)[CH2:13][CH2:12]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(Cl)Cl>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccccc1S
Reactant: COC1CCC(C(=O)O)CC1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Product: COC1CCC(c2nc3ccccc3s2)CC1

Procedure:
A mixture of 2-amino-benzenethiol (796 mg, 6.32 mmol), 4-methoxy-cyclohexanecarboxylic acid (1.0 g, 6.32 mmol) and Lawesson reagent (889 mg, 2.2 mmol) was heated to 160˜190° C. for 1 h. Then the mixture was diluted with DCM (100 ml) and washed with 10% aqueous NaOH solution (2×10 mL), brine, and dried over Na2SO4. The organic layer was concentrated and purified by flash column chromatography to give 2-(4-methoxy-cyclohexyl)-benzothiazole which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:22]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:22])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccn1
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccn1
Temperature: 150 °C

Procedure:
A mixture of 2.4 g of 4-chloro-1-(2-pyridylmethyl)-1H-imidazo[4,5-c]quinoline and 50 mL of 15% ammonia in methanol was placed in a bomb and heated at 150° C. for 6 hours. After cooling, the reaction mixture was filtered. The solid was slurried with aqueous sodium bicarbonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278°-284° C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275°-281° C. The two crops were combined for analysis. Analysis: Calculated for C16H13N5 : C, 69.8; %H, 4.8; %N, 25.4; Found %C, 69.7; %H, 4.8; N, 25.2.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[CH3:37][CH:38]([CH:41]([CH3:43])[OH:42])CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:15][CH2:16][C:17]3([O:42][CH:41]([CH3:43])[CH:38]([CH3:37])[O:20]3)[CH2:18][CH2:19]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(O)C(C)CO
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
A mixture of 4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), 2,3-dimethylpropane-1,3-diol (0.56 g), p-toluenesulfonic acid monohydrate (0.036 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:10]1[CH2:11][CH2:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:15])([O:13][CH3:14])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Yield: 79.8 %

Procedure:
Preparation according to Preparation 14. 3-(3-Chloro-2-fluorophenyl)-3-methoxypyrrolidine (3.44 g, 15 mmol), dry dimethyl formamide (5 mL), sodium hydride (60% dispersion in mineral oil, 0.720 g, 18 mmol). Benzylbromide (1.78 mL, 15 mmol) in dry dimethyl formamide (5 mL). Work up according to Preparation 14. Purification by flash column chromatography on silica gel (ethyl acetate) gave the title compound (3.83 g, 80%). MS m/z (rel. intensity, 70 eV) 304 (14), 289 (16), 133 (65), 132 (35), 91 (bp).