Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:36][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylamine (20 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)=[C:2]3[Cl:1])[OH:13])[CH2:15][CH2:16]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc2ccc(C(O)C3CCNCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2ccc(C(O)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(piperidin-4-yl)methanol (74 mg, 0.16 mmol, Intermediate 11: step b) in DCM (3 mL) was added Et3N (24 L, 0.18 mmol) and the resulting solution cooled to 0° C. Then acetic anhydride (16 μL, 0.17 mmol) was added dropwise and the reaction stirred at 0° C. for 30 minutes. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated to dryness and purified by reverse-phase HPLC (acetonitrile/water+ TFA). The acidic fractions were neutralized by diluting with EtOAc and washing with saturated aqueous NaHCO3. The organics were concentrated to dryness, dissolved in 1/1 acetonitrile/water and lyophilized to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-7.99 (m, 1H), 7.84-7.80 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 5.49 (s, 1H), 4.57-4.50 (m, 1H), 4.43-4.30 (m, 3H), 4.01 (s, 3H), 3.83-3.71 (m, 1H), 2.94-2.84 (m, 1H), 2.40-2.33 (m, 1H), 1.94 (d, J=8.2 Hz, 3H), 1.84-1.72 (m, 2H), 1.32-1.19 (m, 2H), 1.16-1.03 (m, 1H). MS (ESI): mass calcd. for C26H26ClF3N2O3, 506.2; m/z found, 507.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:26]=[O:27])[C:20]([OH:25])=[C:21]([CH:23]=[O:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:26]=[O:27])[C:20]([O:25][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:21]([CH:23]=[O:24])[CH:22]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)c(OCCCCCCCCc2ccccc2)c(C=O)c1
Temperature: 80 °C

Procedure:
8-Phenyloctyl bromide (2.69 g, 10 mmol) was added to a stirred mixture of 5-methyl-2-hydroxy-1,3-benzenedicarboxaldehyde (1.64 g, 10 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in dry dimethylformamide (20 ml) at room temperature under nitrogen. The suspension was heated to 80° C. for 3 hours then allowed to cool. Water (40 ml) was added and the mixture extracted with diethyl ether (2×40 ml). The extracts were dried, filtered and evaporated to a yellow solid. Recrystallisation from methanol (25 ml) gave the title product as pale yellow crystals, m.p. 59° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:55]=[C:56]([CH:64]3[CH2:69][CH2:68][N:67]([C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:66][CH2:65]3)[N:57]3[C:62]=2[C:61]([NH2:63])=[N:60][CH:59]=[N:58]3)[CH:50]=[C:51]([F:53])[CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
The solution of N,N-dimethylglycine (100 mg, 0.24 mmol) in DCM (1 mL) was treated with N,N-diisopropylethylamine (83 uL, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol) and 1-hydroxybenzotriazole (38.8 mg, 0.29 mmol) followed by 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol). The mixture was stirred at rt overnight then purified by HPLC. 20 mg (17%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.91 (s, 1H), 7.47-7.35 (m, 5H), 6.88 (s, 1H), 6.82 (d, 1H), 6.75 (d, 1H), 6.50 (s, 1H), 5.49 (s, 2H), 5.13 (s, 2H), 4.66 (d, 1H), 4.23 (d, 1H), 3.48 (m, 1H), 3.25-3.15 (m, 2H), 3.12-3.04 (m, 1H), 2.76 (td, 1H), 2.29 (s, 6H), 2.17 (s, 2H), 1.72-1.61 (m, 2H); LC-MS m/z [M+H]+ 503.3, RT 2.34 min.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([F:10])=[CH:19][CH:18]=2)[C:14]([C:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH:25]=2)=[CH:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
Benzoyl chloride (33.3 mg, 0.24 mmol) was added to a solution of 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4b, 49.6 mg, 0.215 mmol), triethylamine (0.15 mL, 1.1 mmol) and DMAP (5 mg) in dichloromethane (2 mL). The mixture was stirred at room temperature prior to quenching with water and extraction into dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. Purification by flash chromatography (silica gel, 2M methanolic ammonia in chloroform) yielded 1-benzoyl-5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (27.8 mg, 39%, HRMS-FAB+ for C21H20N2OF calculated MH+ : 335.15598; found: 335.15457).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:28]([CH2:36][CH3:37])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[N:32][C:31]=12.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.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.O>[NH:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:27]2[N:28]([CH2:36][CH3:37])[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=23)=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(Oc3nc4ccccc4[nH]3)cc2)OC1(C)C
Reactant: CCn1nc2cccnc2c1Br
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc2cccnc2c1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazole (116 mg), 3-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (71 mg), tetrakis(triphenylphosphine)palladium(0) (36.3 mg), cesium carbonate (153 mg) and DME/water (3/1, 4 ml) was subjected to microwave irradiation at 120° C. for 40 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (66.0 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13]C(=O)C)=[CH:8][N:7]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H-]>O1CCCC1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(COC(C)=O)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(CO)nc1
Reaction time: 1 h

Procedure:
2,5-Di(acetoxymethyl)pyridine (0.05 mole) is reduced with lithium aluminum hydride (0.025 mole) in tetrahydrofuran (50 ml.) at 0° C. with stirring. After one hour, water is added to decompose excess hydride, and the mixture is concentrated to dryness. The residue is extracted with hot isopropanol (2×60 ml.) and the extract is concentrated to dryness to give 2,5-di(hydroxymethyl)pyridine.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:28])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:14]([Cl:28])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Product: COC(=O)COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.78 g (5 mmol) of 3-(1-adamantyl)-4-methoxycarbonylmethyloxybenzoic acid and 15 ml of thionyl chloride were introduced into a round-bottomed flask and the mixture was heated at reflux for one hour. It was evaporated to dryness and the crude acid chloride, which was used without further purification in the remainder of the synthesis, was recovered.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].C1C(=O)N([Br:23])C(=O)C1>C1COCC1>[Br:23][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a -78° C. solution under nitrogen of 1-triisopropylsilylpyrrole (2.8 g, 12.6 mmol) in THF (30 ml) was added NBS (2.23 g, 12.6 mmol) via a solid addition funnel. The reaction mixture was stirred at -78° C. for 1 hour and then was warmed to ambient temperature over 1 hour. The reaction mixture was concentrated, carbon tetrachloride was added to precipitate the succinimide and the solid was filtered and washed with carbon tetrachloride. The filtrate was concentrated, and the crude product was purified by flash chromatography (hexanes) to afford 3-bromo-1-triisopropylsilylpyrrole (3.18 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:2].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(#N)C.C(OCC)(=O)C.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.[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]#[C:1][C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2
Reactant: C#CC12CCCC(NC(=O)OC(C)(C)C)(CC1)C2
Reactant: Clc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC12CCCC(C#Cc3ccccn3)(CC1)C2
Temperature: 70 °C
Yield: 76.3 %

Procedure:
To a stirred solution of tert-butyl 5-ethynylbicyclo[3.2.1]octan-1-ylcarbamate (5.8 g, 23.3 mmol) and 2-chloropyridine (3.18 g, 28 mmol) in TEA (30 mL) and acetonitrile (150 mL) under N2 was added Pd(PPh3)4 (266 mg, 0.23 mmol), followed by CuI (266 mg, 1.4 mmol). The reaction mixture was heated at 70° C. for three hours. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (250 mL), washed with water (150 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 5.8 g (76%) of the title compound, tert-butyl 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-ylcarbamate, as a white solid. ESI-MS m/z: 298 (M-55)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[S:57][C:58]([S:62](Cl)(=[O:64])=[O:63])=[C:59]([CH3:61])[N:60]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:58]2[S:57][C:56]([CH3:55])=[N:60][C:59]=2[CH3:61])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)s1
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride as starting materials in 22% yield. LCMS for C29H32ClN8O3S2 (M+H)+: m/z=639.2.
Reaction SMILES: [C:1]1([CH:7]([NH2:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][CH2:13][NH:14][C:15]([NH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[CH:9])=[O:16]
Reactant: C#CC(N)c1ccccc1
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(NC(=O)NCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 180 mg of 1-phenyl-prop-2-ynylamine (Formula 28) in 5 mL of CH2Cl2 were added 0.1 mL of 2-chloroethyl isocyanate and 0.2 mL of triethylamine. After the mixture was stirred at room temperature for 2 hours, the solvent was removed. Column chromatography (50% ethyl acetate/hexane) gave 153 mg of 1-(2-chloro-ethyl)-3-(1-phenyl-prop-2-ynyl)-urea (Formula 29) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.46 (m, 1H), 3.45-3.49 (m, 2H), 3.52-3.54 (m, 2H), 5.40-5.41 (m, 1H), 5.55-5.57 (m, 1H), 5.74-5.76 (m, 1H), 7.27-7.35 (m, 3H), 7.48-7.50 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].O.Cl>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3noc(C)c23)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(O)cc3)c12
Temperature: 100 °C
Yield: 53.7 %

Procedure:
To 1.05 g of 4-(4-methoxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one (4.08 mmol) in 15 mL dry DMF was added 1.03 g of sodium ethanethiolate in 15 mL dry DMF at room temperature. The reaction was then heated at 100° C. for 2.5 h. Added water and 1M HCl until acidic. Extracted the product with diethyl ether and dried the extracts with Na2SO4, filtered, and concentrated in vacuo. The product was purified via silica gel chromatography eluting with 95:5 dichloromethane:methanol to give 533 mg of 4-(4-hydroxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one; Mp 268-276° C.; MS m/z 216 (M−N2+H).
Reaction SMILES: I[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.[CH3:19][O:20][C:21]1[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][C:24]([C:42](=[O:47])N(OC)C)=[CH:23][N:22]=1>CCOCC>[CH:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([C:42]([C:24]2[CH:25]=[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:21]([O:20][CH3:19])=[N:22][CH:23]=2)=[O:47])=[CH:3]1)([CH3:13])[CH3:12]
Reactant: COc1ncc(C(=O)N(C)OC)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)n1cc(I)c2cnccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ncc(C(=O)c2cn(C(C)C)c3ccncc23)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1-isopropyl-1H-pyrrolo[3,2-c]pyridine (Preparation 45, 250 mg, 0.875 mmol) in ether (5 mL) at −78° C. was added nBuLi (2.3M in hexane, 0.38 mL, 0.875 mmol) and the reaction stirred at this temperature for 30 minutes. A solution of di-tert-butyl {2-methoxy-5-[methoxy(methyl)carbamoyl]pyridin-3-yl}imidodicarbonate (Preparation 69, 300 mg, 0.729 mmol) in ether (2 mL) was added and the reaction continued to stir at this temperature for another 30 minutes. The reaction was warmed to room temperature for 2 hours before being quenched by the addition of saturated ammonium chloride solution. The reaction was extracted into EtOAc (3×15 mL), the combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with EtOAc:DCM 50:50 to afford the title compound and taken on to the next step directly.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH3:23])[O:17]1.[F:25][C:26]([F:33])([F:32])[C:27]([O:29]CC)=[O:28].CC(O)=O>C1COCC1>[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH2:23][C:27]([OH:29])([OH:28])[C:26]([F:33])([F:32])[F:25])[O:17]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C=C(CC(O)(O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of hexamethyldisilazane (167 mL, 800 mmol) in THF (200 mL) at 0° C. was cannulated n-BuLi (500 mL, 800 mmol) and the mixture was stirred at 0° C. for 30 min, then cannulated into a solution of freshly distilled 2,2,6-trimethyl-1,3-dioxin-4-one (56.9 g, 400 mmol) in THF (400 mL) at −78° C., keeping the internal temperature below −60° C. Stirring was continued at −78° C. for 1 h, then a solution of ethyl 2,2,2-trifluoroacetate (52.5 mL, 440 mmol) in THF (100 mL) was added quickly (<1 min; internal temperature remained below −70° C.). The cooling bath was removed and stirring was continued at −78 to 0° C. for 2 h. Cooled to −45° C., then HOAc (57.3 mL, 1000 mmol) was added and the mixture was warmed to −10° C. Poured into ice cold 0.5 M HCl (pH 1), extracted with TBME, washed with sat. NaHCO3-sol., icecold 0.5 M HCl and brine, dried over Na2SO4. Removal of the solvent in vacuum (bath temperature below 40° C.) left a yellow oil, added THF (ca. 200 mL), toluene (ca. 50 mL) and H2O (ca. 20 mL) and evaporated to dryness to give the title compound as a light yellow solid (89.27 g, 87%). MS (ISN) 237.0 [(M−H)−].
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[C:7]#[N:8]>N1C=CC=CC=1>[C:13]1([C:10]2[CH:9]=[C:6]3[C:7]([NH2:8])=[N:3][NH:2][C:5]3=[N:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN
Reactant: N#Cc1cc(-c2ccccc2)cnc1Cl
Solvent: c1ccncc1
Solvent: O
Product: Nc1n[nH]c2ncc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (1.42 g, 28 mmol) was added to a stirred solution of 2-chloro-5-phenylnicotinonitrile (2.45 g, 11.4 mmol) in pyridine (25 ml). The reaction mixture was stirred at reflux for 6 hours, cooled and the resulting solid was filtered and dried in vacuo, affording the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>CCOCC.Cl[Ni](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>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1

Procedure:
4-chloro-2-isopropylindene (10 g, 54 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Dimethylphenylmagnesium bromide (54 mmol) as a Et2O solution was added under vigorous stirring and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.5 g (39%).