Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[CH:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(OC)(C)C>[C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)CCC=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CCCC1=CCCC1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 5-cyclopentylidene-2-pentanone (9.92 g; 65 mmol) and p-TsOH (100 mg; 0.53 mmol) in toluene (150 ml) was heated at 90° C. for 8 hours, then cooled down to room temperature, diluted with MTBE (100 ml), washed with saturated NaHCO3 (50 ml), H2O (50 ml), brine (50 ml), dried over MgSO4 and concentrated in vacuo. Distillation under reduced pressure (48° C./0.065 torr) yielded 7.13 g of 5-(cyclopent-1-enyl)-2-pentanone (purity about 80%), which was further purified by flash chromatography to give 6.1 g (61% yield) of a 89% pure product containing 11% of 5-cyclopentylidene-2-pentanone.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([NH:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:21])[C:6]([NH:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(NC)nc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(NC)nc1C
Yield: 56 %

Procedure:
Phenyl N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][C:13](=O)[C@@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][CH2:13][C@@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1
Reactant: C[C@H]1NCc2cc(Br)cnc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CNc2ncc(Br)cc2CN1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
To a cooled solution (0° C.) of LAH (1M in THF, 4.4 mL, 4.4 mmol) was added a solution of (R)-7-bromo-3-methyl-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (750 mg, 2.9 mmol) in THF (20 mL). The reaction was warmed to room temperature and stirred over night. Once the reaction was complete, it was cooled to 0° C. and carefully quenched with water (10 mL), extracted with ethyl acetate (4×15 mL), dried over sodium sulfate and concentrated. The product was isolated by column chromatography (10% MeOH in CH2Cl2) to give the title compound as a light yellow solid (161 mg, 23%): 1H NMR (400 MHz, CD3OD) δ 7.96 (s, 1H), 7.55 (s, 1H), 3.93-3.89 (d, J=15.6 Hz, 1H), 3.74-3.70 (d, J=15.2 Hz, 1H), 3.43-3.39 (d, J=13.6 Hz, 1H), 3.02 (m, 1H), 2.81-2.76 (m, 1H), 1.14-1.12 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([N:15]1[CH2:20][CH2:19][O:18][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)([CH2:21][CH2:22][OH:23])[CH2:16]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:7]([N:15]1[CH2:20][CH2:19][O:18][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)([CH2:21][CH:22]=[O:23])[CH2:16]1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCOC(CCO)(c2ccc(F)c(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCC1(c2ccc(F)c(F)c2)CN(C(=O)c2ccccc2)CCO1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A solution of 0.32 ml of oxalyl chloride in 7.3 ml of DCM is cooled to −78° C. under a nitrogen atmosphere and a solution of 0.51 ml of DMSO in 3.5 ml of DCM is added dropwise, followed by a solution of 1 g of the compound obtained in step A of EXAMPLE 27 in 7.5 ml of DCM and 0.7 ml of DMSO. The reaction mixture is stirred for 30 minutes at −60° C., 2 ml of triethylamine are then added and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is washed with 1 N HCl solution, with saturated Na2CO3 solution and with water, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.03 g of the expected product in the form of an oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC=CC=1C(O)=O.BrC1C=CC=CC=1C.C([Li])CCC.C(=O)=O.[Cl:36]C1C=CC(Br)=CC=1>>[Cl:36][C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: Cc1ccccc1Br
Agent: Cc1ccccc1C(=O)O
Agent: O=C=O
Product: O=C(O)c1ccc(Cl)cc1
Yield: 90 %

Procedure:
Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f. describes the synthesis of benzoic acid derivatives by lithiation of the corresponding aryl bromides and subsequent carboxylation. The preparation of 2-methyl-benzoic acid by reaction of o-bromotoluene with n-butyllithium and subsequent carboxylation with solid CO2 achieves a yield of 83.8%. The reaction of 4-chlorobromobenzene with n-butyllithium and CO2 gives 4-chlorobenzoic acid with a 90% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]2[CH2:22][CH2:23][C:24]3[C:25]([C:36]([NH2:38])=[O:37])=[N:26][N:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:28]=3[C:20]=2[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[CH:40]=[CH:39][C:21]3[CH2:22][CH2:23][C:24]4[C:25]([C:36]([NH2:38])=[O:37])=[N:26][N:27]([C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)[C:28]=4[C:20]=3[CH:19]=2)=[O:16])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(N2CCOCC2)ccc1Cl
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3nc(N4CCOCC4)ccc3Cl)cc1-2

Procedure:
The title compound was synthesized from 0.294 g of 3-chloro-6-morpholinyl-2-pyridine carboxylic acid (from step 1) and (0.258 g) of the title compound of example 244 by the same procedure used for Example 211 except that HATU was replaced by HBTU (BF4). The title compound is a brown solid (0.37 g, 84%), m.p. 252–254° C. Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDCl3): δ 2.95 (m, 2H), 3.12 (m, 2H), 3.48 (m, 4H), 3.88 (m, 4H), 5.39 (s, 1H), 6.65–6.82 (m, 3H), 7.16 7.18–7.23 (m, 3H), 7.43–756 (m, 3H), 7.62 (m, 1H), 9.18 (s, 1H). ESI mass spectrum for C28H25ClFN6O3+: 547 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[Br:17])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:17][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[NH2:7]
Reactant: COc1cc(C)c(Br)c(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(Br)c(N)c1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 99.5 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester ((Example 198: step b) 3.00 g, 9.49 mmol) in CH2Cl2 (50 mL) was treated with trifluoroacetic acid (7.00 mL) dropwise. The solution was stirred at room temperature 1.3 h. The solvents were evaporated in vacuo to yield the product 2-bromo-5-methoxy-3-methyl-phenylamine (2.04 g, 65%) as a yellow solid trifluoroacetate salt. The crude mixture was used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccc(C)c(NC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00040 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00040 mol) and EDCI.HCl (0.138 g, 0.00072 mol) at ambient temperature. After 2 minutes (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 96.91%, 1H NMR (DMSO-d6): δ 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (t, 2H), 7.4 (t, 1H), 7.1 (s, 1H), 6.8 (d, 1H), 6.5 (s, 1H), 6.3 (d, 1H), 4.4 (d, 2H), 4.2 (bs, 2H), 3.9 (d, 1H), 3.6 (bs, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.0 (s, 3H), 1.9 (d, 1H), 1.5 (d, 1H), 1.3 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.C([O-])([O-])=O.[K+].[K+].[CH2:31]1COC[CH2:32]1>[Cl-].C([N+](CC)(CC)CC)C.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]1([C:9]2[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]3[N:5]([N:4]=[CH:3][C:2]=3[CH:31]=[CH2:32])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: C=Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12

Procedure:
400 mg 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 31), 504 mg tributyl(vinyl)stanane, 176 mg tetraethylammonium chloride, 147 mg K2CO3 and 19 mg Pd(PPh3)2Cl2 are suspended in 10 ml THF under a nitrogen atmosphere. The mixture is heated (microwave irradiation) to 110° C. for 45 min. This mixture is worked up by diluting with water and extraction with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated to yield the crude product, which is purified by chromatography on silica gel (ethyl acetate/dichloromethane).
Reaction SMILES: [C:1]([C:3]1(C(O)=O)[C:5]([CH3:7])([CH3:6])[CH:4]1[CH:8]=[C:9]([Cl:11])[Cl:10])#[N:2].N>CN(C)C=O.O>[Cl:10][C:9]([Cl:11])=[CH:8][CH:4]1[C:5]([CH3:6])([CH3:7])[CH:3]1[C:1]#[N:2]
Reactant: CC1(C)C(C=C(Cl)Cl)C1(C#N)C(=O)O
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(C#N)C1C=C(Cl)Cl
Temperature: 130 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
1-Cyano-2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid (1.5 g) was dissolved in dimethylformamide (10 ml) and the solution was saturated with gaseous ammonia at 20° C. The solution was then stirred at 130° C. for 18 hours, then diluted with water (150 ml) and extracted with pentane. The extracts were dried (MgSO4) and the solvent was removed under reduced pressure to give the required 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane nitrile, yield 82%.
Reaction SMILES: N1CCOCC1.C([O:10][C:11](=[O:38])[C@:12]([S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])([CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[NH2:13])C=C>C1COCC1.C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]1([S:25]([C@@:12]([C:11]([OH:38])=[O:10])([CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])[NH2:13])(=[O:26])=[O:27])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C=CCOC(=O)[C@@](N)(C(Cc1ccccc1)C(=O)O)S(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: N[C@](C(=O)O)(C(Cc1ccccc1)C(=O)O)S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (3.3 ml; 38 mmol) was added to a solution of 2-Naphthalenesulphonyl β-benzyl-L-aspartic acid allyl ester (3--3) (1.73 g; 3.8 mmol) and tetrakis (triphenylphosphine) palladium (0.42 g; 0.37 mmol) in dry THF (40 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 2 h and then evaporated to dryness. The resultant yellow oil was triturated with ethyl acetate followed by filtration of the white solid obtained. The crude product was dissolved in DCM (30 ml) and then washed successively with 2N HCl (30 ml) and brine (30 ml×3). The solution was dried (sodium sulphate). Filtration and evaporation of the solvent gave the product as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[C:15]([C:25]([F:28])([F:26])[F:27])=[CH:14][C:10]=2[C:11]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 53; 112 mg, 0.29 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.10 ml, 0.57 mmol), 3-aminopyridine (40.2 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (50.4 mg, 0.37 mmol) and EDC (109 mg, 0.57 mmol). The reaction was stirred for 3 hours, then the solvent removed in vacuo to give a yellow oil. Purification by MDAP gave the title compound as a white solid. 69 mg.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=O)[CH3:2].[C:11](C1C=CC=CC=1S)(=O)C>C(OC(=O)C)C>[O:10]1[CH:11]=[CH:2][CH:1]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]12
Reactant: CC(=O)c1ccccc1S
Reactant: CC(=O)c1ccccc1O
Solvent: CCOC(C)=O
Product: C1=COC2C=CC=CC2=C1

Procedure:
Alternatively, such a 2-acetylphenol or 2-acetylthiophenol is condensed with ethylacetate and cyclized with dehydration to form a benzo[b]pyran which is then condensed with a Grignard reagent, e.g., ##STR10##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[Cl:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>CO>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[NH:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc(-n2c(NCCN3CCCC3)c(C=O)c3ccccc32)cc1
Yield: 20 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-(2-aminoethyl)pyrrolidine as described in Step 2 of Example 29 to obtain oil. The oil is dissolved in small amount of methanol and treated with 1M ethereal hydrochloric acid. The solvents are removed and the residue is triturated with ether to yield 1-(4-tert-butylphenyl)-2-(2-pyrrolidin-1-yl-ethylamino)-1H-indole-3-carboxaldehyde hydrochloride (20% yield) as a light beige solid. ESI/MS 390 (M+H); RT=3.42 min. NMR 10.68 (1H, s); 7.95 (1H, d, J=9 Hz); 7.67 (2H, d, J=9 Hz); 7.47 (2H, d, J=9 Hz); 7.10 (2H, m); 6.63 (1H, d, J=9 Hz); 3.54 (2H, m); 3.40 (2H, m); 3.21 (2H, m); 2.83 (2H, m); 1.91 (4H, m); 1.35 (9H, s).
Reaction SMILES: C([N:4]1[CH2:12][CH2:11][CH2:10][CH:6]([C:7](Cl)=[O:8])[CH2:5]1)(=O)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:7]([CH:6]2[CH2:10][CH2:11][CH2:12][NH:4][CH2:5]2)=[O:8])=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCCC(C(=O)Cl)C1
Reactant: Fc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCCNC1

Procedure:
Reaction of 1-acetylnipecotoyl chloride with fluorobenzene by the procedures used to prepare the compound of Preparation 1 gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:20][CH3:21])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C(O)C1CCc2cc(O)ccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(O)ccc2O1
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of 60 parts of 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylic acid, 800 parts of ethanol and 5.52 parts of concentrate sulfuric acid was stirred for 3 hours at reflux temperature. The reaction mixture was evaporated. Water was added and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was solidified in petroleumether. The product was filtered off and dried, yielding 48 parts (70%) of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate as a residue (intermediate 21).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:5]([O:18][CH3:19])=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1.[CH3:20]I>CN(C=O)C>[I:3][C:4]1[C:5]([O:18][CH3:19])=[CH:6][C:7]([N:10]([CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:8][CH:9]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)ncc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)OC(C)(C)C)ncc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
Sodium hydride (37.70 mg, 0.9425 mmol) was added to a stirred suspension of tert-butyl N-(5-iodo-4-methoxy-2-pyridyl)carbamate (300 mg, 0.8568 mmol) in DMF (3 mL) and the reaction was stirred at 0° C. for 15 minutes. MeI (145.9 mg, 63.99 μL, 1.028 mmol) was added and the reaction allowed to warm to ambient temperature over 1 hour. The mixture was quenched by the addition of water, diluted with EtOAc and the layers separated. The organic layer washed with saturated aqueous NaHCO3 (×1), brine (×2), dried (MgSO4) filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 30% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-iodo-4-methoxypyridin-2-yl)(methyl)carbamate as a colourless oil (269 mg, 86% Yield). MS (ES+-t-Bu) 309.4.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[Cl:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:30][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:25][C:24]=1[O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-benzyloxy-4-chlorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17ClN4O, 401. Found, 401.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[Cl:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:19][C:20]1[CH:27]=[C:26]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(C=O)c(Cl)c1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (0.100 g, 1 eq) and 2-chloro-4-fluorobenzaldehyde (0.11 g, 2 eq) in dimethylformamide (3 mL) is added cesium carbonate (0.23 g, 2 eq). The reaction is heated to 100° C. overnight. The reaction is cooled to room temperature and water is added. The mixture is extracted with ethyl acetate and the organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 0-10% ethyl acetate:toluene to give 0.101 g of 2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde. ES/MS m/e 426.1 (M+1).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:49]([OH:50])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:51]([CH3:53])[CH3:52])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:51]([CH3:52])[CH3:53])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:49]([OH:50])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
15 mg of compound (40) was dissolved in 2 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with chloroform-methanol (40:1). The fraction containing the desired product was concentrated to dryness to give 11.5 mg of compound (41).