Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=C([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)C=C(S(CCC)(=O)=O)C=1OCCC)C1C=CC=CC=1>C(OCC)(=O)C>[CH3:41][O:40][C:32]1[CH:31]=[C:30]([CH:27]2[CH2:28][CH2:29][CH2:25][O:26]2)[CH:35]=[C:34]([O:36][CH3:37])[C:33]=1[O:38][CH3:39]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCC
Solvent: CCOC(C)=O
Product: COc1cc(C2CCCO2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (±)-trans-2-(3-benzyloxy-4-propoxy-5-propylsulfonylphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (6.35 g, 10.87 mol) in ethyl acetate (50 ml) was added 10% pd/c (0.80 g). The reaction mixture was stirred at room temperature under balloon pressure for 2 h. The Pd/C was filtered through celite and washed with ethyl acetate (80 ml). The filtrate was concentrated and the crude product was purified through silica gel column using Ethyl acetate:light petroleum (1:3) to give (±)-trans-2-(3-hydroxy-4-propoxy-5-propylsulfonylphenyl)-5-(3,4,5-trimethoxyphenyl tetrahydrofuran as a solid (3.30 g, 61%). TLC: Ethyl acetate:light petroleum (3:2), Rf=0.5 ; m.p. 115-117° C.; 1H NMR (CDCl3, 200 MHz): δ 0.95 (t, J=7.72 Hz, 3H), 1.0 (t, J=6.81 Hz, 3H), 1.6-1.95 (m, 6H), 2.3-2.42 (m, 2H), 3.25 (m, 2H), 3.75 (s, 3H), 3.80 (s, 6H), 4.03 (t, J=6.12 Hz, 2H), 5.0-5.13 (m, 2H), 6.28 (s, 1H), 6.5 (s, 2H), 7.18 (d, J=1.54 Hz, 1H), 7.34 (d, J=1.54 Hz, 1H); IR (neat): 3400, 2975, 2945, 2860, 1725, 1540, 1490, 1440 cm−1. FAB Mass: 495 (M+), HRMS:calculated 0.495.205265; found. 495.207215.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[N:10][CH:9]=1.C1COCC1.[OH-].[Na+]>CCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:12][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[CH:9][N:10]=1
Reactant: COC(=O)CCCCc1cnc(-c2ccccc2OC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1-c1ncc(CCCCC(=O)O)o1
Yield: 89.6 %

Procedure:
Combine 5-[2-(2-methoxy-phenyl)-oxazol-5-yl]-pentanoic acid methyl ester (2.1 g, 7.3 mmol) with THF (4 mL), EtOH (4 mL) and 2N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.0-4.0 using aq HCl. Extract the mixture with CH2Cl2 and concentrate the extracts in vacuo. Drying gives 5-[2-(2-methoxy-phenyl)-oxazol-5-yl]-pentanoic acid (1.8 g, 91%). MS (ES): (M+1)+ 274.1, 275.1 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1n[nH]c2c(c1=O)CCCC2
Yield: 61.1 %

Procedure:
To 4-oxo-1,4-dihydrocinnoline-3-carboxylic acid ethyl ester (4.5 g) dissolved in trifluoroacetic acid (20 ml) was added platinum oxide (0.2 g). The reaction mixture was hydrogenated at 50 psi until no further uptake of hydrogen was observed. The catalyst was collected by filtration, the filtrate was poured onto ice, the pH was raised to pH6 with base, the resulting precipitate was collected by filtration, washed with water and dried to give a solid (2.8 g, 61%). δH (250 MHz; DMSO-d6) 1.26 (3H, t, J=7 Hz, CH3), 1.68 (4H, m, CH2), 2.33 (2H, t, J=5.5 Hz, CH2), 2.62 (2H, t, J=5.5 Hz, CH2), 4.25 (2H, t, J=7 Hz, CH2), 13.19 (1H, br s, NH), m/z (ESP+) 223 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: FC(F)(F)c1ccc(Br)c2occc12
Product: CC1CN(Cc2ccccc2)CCC1(O)c1ccc(C(F)(F)F)c2ccoc12
Yield: 38.3 %

Procedure:
Beginning with 1.5 gm (5.7 mMol) 4-trifluoromethyl-7-bromobenzofuran and 1.26 gm (6.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.85 gm (39%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([O:31][C:32]1[C:37]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([CH3:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:35]2[CH:36]=[C:37]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([CH3:49])[CH:43]=3)(=[O:41])=[O:40])[C:32]([O:31][CH2:29][CH3:30])=[N:33][CH:34]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Yield: 30.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with N-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-hydroxy-3-methylbenzenesulfonamide (149 mg, 0.34 mmol), 2M cesium carbonate (340 μl, 0.68 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) according to the method described in Example 3 to give 47 mg (27% yield) of the title compound. Purity 85%.
Reaction SMILES: [O:1]([C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1
Reactant: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 61J (369 mg) in THF (4 mL) was added TBAF (1.0 M in THF, 1.3 mL). The reaction was stirred at rt for 1 h. The reaction was extracted with EtOAc which was washed three times with water, dried over MgSO4, filtered and concentrated. Purification by reverse phase HPLC (Phenoenex Luna 20×100 mm S5 C18, 10 min. grad, 20 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) provided the title compound (186 mg): MS (ES) m/z 306.42 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25]Cl)[CH:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25][N:15]2[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)[CH:22]=[CH:21][N:20]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: O=C(COCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COCc1ccccc1)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Benzyloxyacetyl-piperazine (1.0 equiv) was mixed with the compound 2-chloro-4-(chloro-methyl)pyridine (1.0 equiv) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CC(=O)N1CCCC(C)(C)c2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(8-Amino-5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (93%). LCMS: m/z=551.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=8.6 Hz), 8.01 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.41 (d, 1H, J=1.5 Hz), 7.32 (m, 2H), 6.53 (m, 2H), 4.74 (m, 1H), 3.89 (m, 7H), 3.17 (m, 4H), 2.60 (m, 1H), 2.20 (m, 1H), 1.91 (s, 3H), 1.62 (m, 3H), 1.41 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C@H:15]1[NH:27][C@H:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][N:27]1[C@H:15]([CH3:14])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[C@H:26]1[C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:33]=1
Reactant: COC(=O)/C=C/c1ccc([C@H]2N[C@H](C)Cc3c2[nH]c2ccccc32)cc1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (291 mg, 1.30 mmol) was added to a solution of (E)-methyl 3-(4-((1R,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (300 mg, 0.87 mmol) and N,N-diisopropylethylamine (0.226 ml, 1.30 mmol) in 1,4-dioxane (5 ml). The mixture was stirred at 90° C. for 1 hour then the mixture was evaporated to dryness and the residue was partitioned between DCM (30 nil) and water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the extracts combined with the organic layer. The combined extracts were filtered through a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 15% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (314 mg, 86%) as an off-white solid. 1H NMR (400 MHz, DMSO, 30° C.) δ 0.87 (3H, d), 1.06 (3H, d), 1.9-2.28 (2H, m), 2.55-2.8 (3H, m), 2.97-3.21 (1H, m), 3.72 (3H, s), 4.31-4.69 (2H, m), 4.88 (1H, s), 6.60 (1H, dd), 6.98 (1H, t), 7.04 (1H, t), 7.17-7.35 (3H, m), 7.44 (1H, d), 7.55-7.76 (3H, m), 10.65 (1H, s). m/z: ES+ [M+H]+ 421.
Reaction SMILES: C[OH:2].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=C)[CH:13]([F:27])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:2])[CH:13]([F:27])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A methanol (300 mL) solution of [1-({[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}methyl)vinyl]benzene (2.02 g, 5.95 mmol) was cooled to −70° C. Ozone gas was bubbled through the solution until a blue color appeared. The solution was purged with nitrogen then a solution of triphenylphosphine (2.34 g, 8.92 mmol) in methylene chloride (100 mL) was added. Contents of the reaction flask were warmed to room temperature and the solvent was removed under reduced pressure. The remaining residue was subjected to flash column chromatography (hexane:ethyl acetate, 90:10) to give 2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethanone as a colorless oil (1.68 g, 83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:17]=1[CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:16]=4[F:15])[CH2:24][CH2:23]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(F)cc2)CC1
Reactant: Fc1ccc(F)c(CC2CCNCC2)c1
Product: Fc1ccc([C@H]2CC[C@H](N3CCC(Cc4cc(F)ccc4F)CC3)CC2)cc1

Procedure:
4-(4-Fluorophenyl)cyclohexanone and 4-(2,5-difluorobenzyl)piperidine were reacted as described in example 9 to give the product (36%, mp: 80°-81° C.). Calc'd for C24H28F3N: C, 74.40%; H, 7.29%; N, 3.18%. Found: C, 74.25%; H, 7.29%; N, 3.56%.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([N:10]1[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[O:16])[C:11]1=[O:18])=[O:9])(=O)C.N>C(O)C.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[OH:22])[C:8]([N:10]1[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[O:16])[C:11]1=[O:18])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)N2CCN(C(N)=O)C2=O)cc1OC(C)=O
Agent: N
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCN(C(=O)c2ccc(O)c(O)c2)C1=O
Reaction time: 0.17 h

Procedure:
To a suspension of 6.2 g (0.017 mol) of 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide in 50 ml of a 1:1 mixture of ethanol/water was added dropwise 2.1 ml of ammonia. After stirring for 10 minutes, a clear solution formed from which 3-(3,4-dihydroxybenzoyl)-2-oxo-1-imidazolidinecarboxamide began to crystallize after 15 minutes, yielding 3.8 g.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:18][O:17][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CCC1(CC)c2ccc(OC)cc2C(=O)C1CC=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)c2ccc(OC)cc2-c2c1ccn2C[C@@H](C)O
Reaction time: 0.75 h
Yield: 60.9 %

Procedure:
A solution of 3.9 g of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-diethyl-1-indanone and 120 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator. A solution of 4.5 g of (R)-1-amino-2-propanol in 30 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 2.73 g (61%) of (R)-1-(7-methoxy-4,4-diethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:36]\[C:32]1[NH:33][C:34]([CH3:35])=[C:30]([CH2:29][N:26]2[CH2:27][CH2:28][C@@H:24]([OH:23])[CH2:25]2)[C:31]=1[CH3:38])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CC[C@@H](O)C1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CC[C@@H](O)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-((R)-3-hydroxy-pyrrolidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:46][CH:43]3[CH2:45][CH2:44]3)=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NC1CC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC3CC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and cyclopropylamine (8.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-cyclopropylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.6 mg).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30].O>CN(C)C(=O)C>[NH2:30][C:29]1[N:31]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][CH:4]=[C:5]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:22])([F:21])[F:23])[CH:11]=3)[N:6]=2)[N:28]=1
Reactant: N=C(N)N
Reactant: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.003 mole) of 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide is heated at about 150° C. for 40 hours. After this time, the reaction mixture is poured into 50 mL of water. The resultant solid is collected by filtration and is then slurried in 25 mL of diethyl ether. The solid is again collected by filtration and is then recrystallized from ethanol, yielding 2,4-diamino-6-[3,5-di(trifluoromethyl)phenyl]pteridine.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17](Cl)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2].[F:24][C:25]([F:39])([F:38])[O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+].[F-].[K+]>CS(C)=O.O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[CH:9]([NH:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([N:36]2[CH:37]=[C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:25]([F:24])([F:38])[F:39])[CH:28]=3)[N:34]=[CH:35]2)[N:16]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(Cl)n1
Reactant: FC(F)(F)Oc1cccc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(Cl)nc(-n2cnc(-c3cccc(OC(F)(F)F)c3)c2)n1
Temperature: 25 °C
Yield: 122.2 %

Procedure:
A solution of 2-(2,6-dichloro-pyrimidin-4-ylamino)-4-methylpentanoic acid (3-ethoxypropyl)amide (1.5 gram), 4-(3-trifluoromethoxyphenyl)-1H-imidazole (0.99 gram), K2CO3 (1.7 gram) and KF (0.24 gram) in dimethylsulfoxide (40 ml) was heated to 100° C. for 17 hours. The solution was cooled to room temperature, taken up in water, and extracted three times with ethyl acetate. The etyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (toluene/acetone 4/1) provided 2.8 g of 4-methyl-2-{6-chloro-2-[4-(3-trifluoromethoxyphenyl)-imidazol-1-yl]-pyrimidin-4-ylamino}-pentanoic acid (3-ethoxypropyl)amide as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
22.3 Using general procedure A, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid was coupled with 1-methyl piperazine to give 4-chloro-N-[4-(2-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 505.3 ([M+H]+)
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C)C=O.Cl>[CH:1]1([N:5]([CH3:30])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of the title compound of Step E (170 mg, 0.41 mmol) in dimethylformamide (4 ml) at 0° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1 mmol). The resulting slurry mixture was stirred at 0° C. for about 30 minutes and gradually became a brownish-yellow solution. To this solution at 0° C. was added methyl iodide (0.13 ml, 2 mmol). The resulting solution was warmed to room temperature and stirred for about 19 hours. The solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (3×50 ml), brine, dried, filtered, and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (155 mg). MS (APCl+) Calc: 423.1, found: 424.0 (M+1).