Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=2)[NH:8][CH:7]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(F)cc12)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 70 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-fluoro-1H-indol-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 212, (S)-3-(benzyloxy)-2-(2-(5-fluoro-1H-indol-3-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (78 mg, 70%). 1H-NMR (400 MHz, DMSO-D6): σ 10.98 (s, 1H), 10.17 (s, 1H), 8.37 (d, 1H), 7.63-7.57 (m, 2H), 7.39-7.16 (m, 9H), 7.05-6.95 (m, 4H), 6.93-6.86 (m, 1H), 4.75-4.67 (m, 1H), 4.50 (s, 2H), 3.70-3.53 (m, 4H). MS (EI) for C32H27F2N3O4. found 555.9 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:4]6[N:3]([CH3:2])[CH:7]=[CH:6][N:5]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cn1ccnc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nccn5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(1-Methyl-1H-imidazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (251 mg; compound B93) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (218 mg; compound C10) and HATU (271 mg) in DCM (7 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 52 to afford the title compound after purification by preparative HPLC as a solid.
Reaction SMILES: Cl.[N:2]([CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7])=[N+]=[N-].[H][H].C1C[O:21][CH2:20][CH2:19]1>CO.[Pd]>[C:20]([NH:2][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7])(=[O:21])[CH3:19]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: [N-]=[N+]=NCC(=O)c1ncn2ccsc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution (17 ml) of 10% hydrochloric acid in methanol and 800 mg of 10%Pd—C. were added to a solution of 1.78 g of 7-azidoacetylimidazo[5,1-b]thiazole in 85 ml of methanol and 85 ml of THF. The atmosphere in the reactor was replaced with hydrogen. The system was stirred at room temperature for 5 hr. The catalyst was removed by filtration through Celite and washed with methanol. The solvent was removed by distillation. The residue was dissolved in 50 ml of DMF. Pyridine (3.43 ml) and 1.22 ml of acetic anhydride were added to the solution under ice cooling. The mixture was stirred at the same temperature for 2 hr. Dichloromethane and brine were added to the reaction solution. The mixture was adjusted to pH 10 by the addition of potassium carbonate. The organic layer were separated. The aqueous layer was further extracted five times with dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=40:1 to 20:1) to give 397 mg of 7-acetylaminoacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:16])=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13]
Reactant: CNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CNS(=O)(=O)c1cc(C(=O)c2c(C)[nH]c3ccccc23)ccc1Cl

Procedure:
is obtained as described in Example 10 a) from 2.68 g 4-chloro-3-methylsulfamoylbenzoyl chloride and 1.3 g 2-methylindole in the presence of 2.7 g aluminum chloride in dichloroethane. Colorless crystals, m.p. 246° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[C:16]([OH:18])(=[O:17])[CH3:15].[CH2:19]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)O
Product: c1ccc(CNC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
To an ice-water cooled solution of 65.8 ml of methylene chloride and 18.2 g of potassium carbonate is added 11.3 ml (98.7 mmol) of cyclohexylamine. To this mixture is added dropwise, over a period of 1 hour, a mixture of 5.21 ml (32.9 mmol) of benzyl 2-bromo-acetate and 65.8 ml of methylene chloride. The resultant hazy, white reaction mixture is then stirred at ice-water temperature for 2.5 hours and then at room temperature for 2.5 days. The resultant opaque, white reaction mixture is then partitioned between methylene chloride and water, and the methylene chloride layer is extracted. The aqueous layer is then washed twice with 50 ml portions of methylene chloride and the combined methylene chloride layers are washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution is then filtered and concentrated to yield a clear yellow liquid which is purified via column chromatography employing a mixture of hexane and ethyl acetate (1:1 ratio) as the eluant to obtain the desired compound as a clear, very light yellow liquid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[OH:31])[CH:26]=[O:27])([CH3:22])[CH3:21].O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[O:31][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[CH:26]=[O:27])([CH3:22])[CH3:21]
Reactant: OCCN1CCOCC1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
Triphenylphosphine (5.14 g, 19.58 mmol) was added to a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (4 g, 19.58 mmol) in tetrahydrofuran (40 ml) followed by addition of 2-hydroxyethylmorpholine (2.57 g, 19.58 mmol) and then the dropwise addition of diethylazodicarboxylate (3.41 g, 19.58 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (2×150ml), basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3×150 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to afford 900 mg (14%) of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde as a yellowish oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[O:36])[CH:33]=4)[C:28]([S:43][CH3:44])=[CH:27]3)=[N:24][CH:25]=2)[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[O:36])[CH:33]=4)[C:28]([S:43]([CH3:44])=[O:6])=[CH:27]3)=[N:24][CH:25]=2)[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Solvent: ClCCl
Product: COc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Reaction time: 0.5 h

Procedure:
m-Chloroperoxybenzoic acid (65%; 91.6 mg, 0.345 mmol, 0.8 eq,) was added at 0° C. to a stirred solution of the product 141b) (200 mg, 0.432 mmol, 1.0 eq) in dichloromethane (10 mL). Stirring was continued at this temperature for 30 min and the reaction mixture was then diluted with dichloromethane (10 mL), washed with saturated natrium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica gel; methanol/ethyl acetate=1:9]. White solid. Yield 70 mg (34% of theory). Melting range: 216-220° C. HPLC (method 6): Rt=7.24 min. Mass spectroscopy: m/z: [M+H]+=478.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH2:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([O:29]O)(C)(C)C>C1C=CC=CC=1.[V]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[O:29][CH2:16]2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1
Reactant: CC(C)(C)OO
Agent: [V]
Solvent: c1ccccc1
Product: OC(Cn1cncn1)(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Yield: 62 %

Procedure:
2,3-Bis(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-butene-2-ol (1.0 g) was dissolved in 50 ml of anhydrous benzene and stirred under nitrogen. To this solution was added 0.012 g of vanadium acetonylacetonate. The solution was then refluxed and tert-butyl hydroperoxide (0.44 g dissolved in 5 ml of anhydrous benzene) was added dropwise over 10 minutes. The reaction was refluxed for one additional hour and then cooled to ambient temperature. The benzene was removed in vacuo and the residue chromatographed on silica gel (2% MeOH/CH2Cl2). This yielded a total of 650 mg of diastereomeric products in a 3:1 ratio. Further chromatography resulted in the separation of the diastereomers. The major isomer was a waxy white solid. NMR (CDCl3 /TMS)δ2.60 (d, J=6 Hz, 1H); 3.48 (d, J=6 Hz, 1H); 4.70 (q, J=7 Hz, 2H), 5.25 (s, 1H); 6.8-7.3 (m, 8H); 7.55 (s, 1H); 7.90 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.I[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:12]3[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=[O:15])[C:10]=2[NH:9][CH:8]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Reactant: Nc1cccc2nc[nH]c12
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cccc2nc[nH]c12
Yield: 25 %

Procedure:
Reaction of 4-aminobenzimidazole (prepared by literature methods Rabinowitz, J. L. J. Am. Chem. Soc., 1951, 73, 3030-3037; van der Want, G. M. Rec. Trav. Chim., 1948, 67, 45-51) and 2-iodo-3-nitrobenzoic acid as above gave 2-(3H-benzimidazol-4-ylamino)-3-nitrobenzoic acid (25%, crude). Purification was by treatment with ethereal CH2N2 followed by chromatograph gave methyl 2-(3H-benzimidazol-4-ylamino)-3-nitrobenzoate (18% yield); mp (EtOAc/Et2O) 146-148° C.; 1H NMR [(CD3)2SO] δ 3.69 (s, 3 H, OCH3), 6.54 (br s, 1 H, ArH), 7.00 (t, J=7.9 Hz, 1 H, ArH), 7.11-7.19 (m, 2 H, 2xArH), 8.12-8.20 (m, 3 H, 3xArH), 10.06 (br s, diphenylamine NH), 12.51 (br s, 1 H, imidazole NH). Also isolated was methyl 2-[(3-methyl-3H-imidazol-4-yl)amino]-3-nitrobenzoate (6%); mp (EtOAc) 219-221° C.; 1H NMR [(CD3)2SO] δ 3.40 (s, 3 H, OCH3), 4.09 (s, 3 H, NCH3), 6.71 (d, J=7.6 Hz, 1 H, ArH), 6.96-7.05 (m, 2 H, 2xArH), 7.43 (d, J=8.0 Hz, 1 H, ArH), 7.99 (dd, J=7.7, 1.6 Hz, 1 H, ArH), 8.11 (dd, J=8.3, 1.5 Hz, 1 H, ArH), 8.15 (s, 1 H, ArH), 9.70 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[C:2]([C:27]4[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Brc1c(-c2ccco2)nn2c(NC3CCCC3)cccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(-c2c(-c3ccco3)nn3c(NC4CCCC4)cccc23)ccn1
Temperature: 75 °C
Yield: 23 %

Procedure:
N-[3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine (0.2 g, 0.6 mmol) was dissolved in N,N-dimethylformamide (8 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (0.09 g, 0.64 mmol), dichlorobis(triphenylphosphine)-palladium (II) (0.020 g, 0.03 mmol) and saturated aqueous sodium carbonate (580 μl). The resulting solution was heated in a 75° C. oil bath overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. The product was purified by silica gel chromatography (7:1 hexane:ethyl acetate) to give 50 mg (24%) of N-cyclopentyl-3-(2-fluoro-4-pyridinyl)-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine as a solid. 1H NMR (CDCl3) δ 8.1 (d, 1H), 7.5 (s, 1H), 7.24 (1H), 7.03(s, 1H), 6.96 (d, 1H), 6.75 (d, 1H), 6.5 (m, 1H), 6.01 (m, 2H), 4.0 (m, 1H), 2.19–2.09 (m, 2H); 1.88–1.77 (m, 4H), 1.77–1.64 (m, 2H);MS m/363 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:21]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc2c(c1)CN(C)CC2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The free base isolated from 1.55 g. of rac.- 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is shaken with 1.1 ml. of a 35% formaldehyde solution and the mixture is allowed to stand at room temperature for 2 hours. It is hydrogenated over 1 g. of Raney nickel, filtered from the catalyst, the filtrate is evaporated and the residue is crystallized with ethanolic hydrogen chloride, methanol and ether. Recrystallization from methanol-ether gives rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 244°-146°.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:7][CH2:8][CH3:9])=[CH:5][CH3:6])[CH3:2].[CH3:10][O:11][C:12](=[O:22])[C:13](=[CH:17][NH:18][C:19](=[O:21])[CH3:20])[C:14](=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[C:19]([NH:18][C@@H:17]1[C:13]([C:12]([O:11][CH3:10])=[O:22])=[C:14]([CH3:15])[O:16][C:4]([O:7][CH2:8][CH3:9])([O:3][CH2:1][CH3:2])[C@H:5]1[CH3:6])(=[O:21])[CH3:20]
Reactant: COC(=O)C(=CNC(C)=O)C(C)=O
Reactant: CC=C(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 25 °C

Procedure:
1,1-Diethoxyprop-1-ene (5.0 ml) was added in one portion to a stirred solution of methyl-2-acetylaminomethylene-3-oxobutanoate (5.2 g) in toluene (15 ml) at 20°-25° C. An exothermic reaction ensued and a crystalline solid precipitated out. The reaction mixture was stirred for 2 further hours at ambient temperature and the solid was then filtered off to give methyl trans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (4.0 g), m.p. 152°-154° C. The structure of this ester was ascertained using X-ray analysis. The n.m.r. spectrum in deuterochloroform showed a signal for the --CH(N)--proton at 4.85 ppm (doublet of doublets of quartets, J3,4 =1.5, J4,NH =9.8, J4,7 =0.9 Hz, C6Me=C7).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:10][CH:11](Br)[CH3:12])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1>>[C:14]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(/[CH:10]=[CH:11]/[CH3:12])[C:8]#[N:9])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(Br)CC(C#N)(c1ccccc1)c1ccccc1
Solvent: C1CCNC1
Product: C/C=C/C(C#N)(c1ccccc1)c1ccccc1

Procedure:
A solution of 10.0 parts of 2,2-diphenyl-4-bromopentanenitrile in 47 parts pyrrolidine is heated to reflux for 17 hours under a nitrogen atmosphere. Then, the solution is cooled, and stripped in vacuo to leave a brown oil which is partitioned between ethyl ether and dilute hydrochloric acid. The ether phase is separated, washed with dilute sodium bicarbonate, dried over anhydrous sodium sulfate, and stripped in vacuo. The residual liquid is then distilled to afford, as a colorless liquid, 2,2-diphenyl-3-trans-pentenenitrile, boiling at about 115°-123° C. at 0.1 mm pressure. This compound is represented by the following structural formula. ##STR6##
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)(=[O:3])[CH3:2].CC(C)=O.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)C.[NH4+].[Cl-]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5.0 g (0.022 mole) of the methyl ketone 2acetylpyrazolo[1,5-c]quinazolin-5(6H)-one prepared as in Example 4A is suspended under argon in dry distilled tetrahydrofuran (100 ml) and treated quickly with 7.0 ml (~1.0 equivalent) of 3M C6H5MgBr/ethyl ether. The mixture is stirred for 5 minutes and another 15 ml (~2 equivalents) of the Grignard reagent is quickly added. The reaction mixture (dark brown) is stirred at room temperature for 30 minutes and then refluxed for another 30 minutes, cooled down to room temperature and the resulting reddish solution is treated with 8.0 ml of saturated NH4Cl solution. The mixture is diluted with 70 ml tetrahydrofuran and stirred at room temperature for ~1 hour. The inorganic salts are filtered off and washed well with tetrahydrofuran (30 ml) and CHCl3 (50 ml). The filtrates are combined and stripped to dryness. Yield: 8.4 g; 3 spots on TLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2F)[N:3]=1.[Cl:29]C1N=CC(C(F)(F)F)=C(Cl)N=1.C(OP(CC1C=CC(N)=C(Cl)C=1)(=O)OCC)C>>[Cl:29][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(F)c1)OCC
Agent: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(Cl)c1)OCC
Yield: 30 %

Procedure:
Prepared analogously to Compound 22C using 2,6-Dichloro-5-trifluoromethylpyrimidine (2.2 g, 10.3 mmol) and (4-amino-3-chlorobenzyl)phosphonic acid diethyl ester (Compound 24D, 2.2 g, 7.94 mmol) to afford 1.1 g of the title compound (30%). 1H NMR (400 MHz, CDCl3): δ=1.22-1.26 (m, 6H), 3.1 (d, J=22 Hz, 2H), 3.99-4.08 (m, 4H), 7.23 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.83 (brs, 1H), 8.3 (d, J=8.2 Hz, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: O=CCCc1ccc(Cl)cc1Cl
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1nc(C)n2c1C(CCc1ccc(Cl)cc1Cl)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dichloro-phenyl)-propionaldehyde. LC-MS: tR=0.64 min.; [M+H]+=324 g/mol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([OH:43])=O.C(N(C(C)C)CC)(C)C.[NH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([NH:53][C:54]1[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=1)=[O:43]
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 5-amino-2-trifluoromethylpyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes→7:93 EtOAc:hexanes) to afford 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 10.93 (s, 1H), 9.23 (d, J=1.9 Hz, 1H), 8.60 (dd, J=6.8, 1.4 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J=7.1, 1.5 Hz, 1H), 6.04 (dd, J=8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H); ESIMS found for C19H16BrF3N4O2 m/z 470.0 (M+H).