Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19](Br)=[CH:20][N:21]=2)[N:18]=1)=[O:5])=C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.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>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:19]1[N:17]2[N:18]=[C:13]([N:12]3[CH2:11][C@@H:7]4[CH2:8][CH2:9][CH2:10][N:6]4[C:4]3=[O:5])[CH:14]=[CH:15][C:16]2=[N:21][CH:20]=1
Reactant: COc1ccccc1B(O)O
Reactant: C=COC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1cnc2ccc(N3C[C@@H]4CCCN4C3=O)nn12
Temperature: 150 °C
Yield: 64.4 %

Procedure:
A mixture of (S)-2-[(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-pyrrolidine-1-carboxylic acid vinyl ester (125 mg, 0.34 mmol), (2-methoxyphenyl)boronic acid (67.2 mg, 0.44 mmol), K2CO3 (141 mg, 1.02 mmol) and dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.017 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction was repeated at 140° C. After removal of the water the reaction mixtures was combined and diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (S)-2-[3-(2-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (76.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.51 (m, 1H) 1.89-2.02 (m, 1H) 2.05-2.18 (m, 2H) 3.18-3.26 (m, 1H) 3.72-3.96 (m, 6H) 4.09-4.16 (m, 1H) 7.04-7.13 (m, 2H) 7.35-7.42 (m, 1H) 7.90-7.96 (m, 1H) 8.03-8.10 (m, 2H) 8.40 (dd, J=9.85, 2.78 Hz, 1H). LRMS (ESI) m/z 350.2 [(M+H)]+, calc'd for C19H19N5O2: 349.4.
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[NH2:7][CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][C:9]([NH2:12])([CH3:11])[CH2:8][NH:7][C:5](=[O:4])[CH3:6]
Reactant: CC(C)(N)CN
Reactant: CCOC(C)=O
Product: CC(=O)NCC(C)(C)N
Temperature: 100 °C
Yield: 57.4 %

Procedure:
A mixture of 26.4 g (0.3 mol) of ethyl acetate and 79.2 g (0.9 mole) of 1,2-diamino-2-methylpropane was heated at 100° C. in a pressured bomb for 36 hours. The reaction mixture was evaporated in vacuo and distilled to give 22.4 g (57.4%) of product which had a boiling point of 100° C. at 0.1 mmHg. This product was identified by NMR and IR spectroscopy.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:18]1([CH2:24]O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:17][C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g (8.2 mmol) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), 0.978 g (9.0 mmol) phenyl-methanol (commercially available), 3.16 g (9.8 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 1.24 g (12.3 mmol) NEt3 in 10 mL DMF was stirred at room temperature for 1 h. The mixture was evaporated to dryness and extracted with DCM and Na2CO3 aq. The combined organic phases were dried with MgSO4 and evaporated. The residue was treated with 100 mL 4N HCl in dioxane at room temperature for 4 h. The mixture was evaporated to dryness to yield trans-4-amino-cyclohexanecarboxylic acid benzyl ester (MS (m/e): 360.4 (MH+)) which was used without further purification. 150 mL DCM was added, 2.95 g (14 mmol) 4-cyano-benzenesulfonyl chloride (commercially available) and 6.17 g (61 mmol) NEt3 and the mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM and 1N HCl aq. and the combined organic phases were evaporated. The residue was recrystallized from methanol to yield 1.9 g (58%) of the title compound. MS (m/e): 397.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:24]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:12]3[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])(=[O:27])[NH2:25]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 410.1 [(M−H)−]; mp 306° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=O)[CH2:3]1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:4]1[CH2:3][C:2]([CH3:1])([CH3:10])[CH2:9][C:7](=[O:8])[CH:6]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: Nc1ccccc1Cl
Product: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with ispropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152°C. Elementary analysis: C14H16NOCL Calcd. C, 67.32; H, 6.45; N, 5.60 Found C, 67.13; H, 6.31; N, 5.82 (b) A mixture of 40 parts of dimedone and 36.4 parts of 2-chloroaniline is heated at 170°-175°C for 45 minutes followed by cooling. The resulting reaction product is recrystallized to obtain yellow cubes. The crystals are collected by filtration, washed well with isopropyl ether and recrystallized from acetone. The procedure yields colorless prisms of 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one. Melting point: 150°-152°C. By procedures similar to those described in Example 1-(a) and (b), the following compounds are produced.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[N:39]1([CH2:45][CH2:46][O:47][C:48]2[CH:49]=[C:50]([NH2:54])[CH:51]=[CH:52][CH:53]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:54][C:50]1[CH:51]=[CH:52][CH:53]=[C:48]([O:47][CH2:46][CH2:45][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:49]=1)=[N:6]2
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(Nc3cccc(OCCN4CCOCC4)c3)ncc12
Yield: 24.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)amine (38 mg, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-N-(3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (18 mg) as a yellow solid. MS m/z 431 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:7][CH:8]=1
Reactant: O=Cc1ccc(C(F)(F)F)cn1
Reactant: NCCCN
Solvent: c1ccccc1
Product: NCCCNCc1ccc(C(F)(F)F)cn1
Yield: 75.1 %

Procedure:
5-Trifluoromethylpicoline aldehyde (3.5 g) was added dropwise at room temperature to a solution of trimethylenediamine (7.4 g) in benzene (70 ml). After the addition, the mixture was gradually heated with stirring, and then while separating water as an azeotrope, refluxed for 2 hours. Benzene was distilled off under reduced pressure, and then the residue was dissolved in ethanol (100 ml). With stirring at 10° to 15° C., sodium borohydride (0.9 g) was added little by little. The mixture was then stirred at room temperature for 2 hours. Ethanol was distilled off at less than 30° C. Dichloromethane was added to the residue, and a portion of it soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure, and volatile materials were removed at 1 mmHg and less than 60 ° C. to give N-(5-trifluoromethyl-2-pyridylmethyl)trimethylenediamine (3.5 g)as a colorless oil. nD20 1.4651
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC1C=CC(O)=CC=1.C1(O)C=CC=CC=1.O(CCC(O)=O)C1C=CC=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:53][CH2:54][CH2:55][CH2:56][N:57]1[CH:61]=[CH:60][N:59]=[CH:58]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]([NH:53][CH2:54][CH2:55][CH2:56][N:57]2[CH:61]=[CH:60][N:59]=[CH:58]2)=[O:11])=[CH:12][CH:13]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)CCOc1ccc(Cl)cc1
Agent: O=C(O)CCOc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: Oc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: O=C(CCOc1ccc(Cl)cc1)NCCCn1ccnc1

Procedure:
A solution of 3-(4-chlorophenoxy)propionic acid (5.0 g, prepared from 4-chlorophenol by the process described in J.A.C.S. 1923, 2708 for the conversion of phenol into 3-phenoxypropionic acid) in THF (90 ml) was treated with 1,1′-carbonyldiimidazole (4.05 g) at room temperature with stirring. The mixture was stirred at ambient temperature for two hours. 1-(3-Aminopropyl)imidazole (3.12 g) was added and the mixture was stirred at ambient temperature for 18 hours. The solvent was distilled off and the residue was dissolved in dichloromethane, washed with water, dried and then evaporated to give a solid which was recrystallised from ethyl acetate to give 3-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]propionamide, m.p. 114-115.5° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O.O>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:11][C@H:7]2[CH2:6][N:44]=[N+:45]=[N-:46])=[O:33])=[CH:41][CH:40]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g ) in dimethylformamide (120 ml), a solution (12 ml) of sodium azide (3.50 g: 53.8 mmole) in water is added. The mixture is stirred at 80° C. for 8 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine and concentrated. The residue is purified by silica gel column chromatography to give (2S, 4S)-1-p-methoxybenzyloxycarbonyl-2-azidomethyl-4-tritylthiopyrrolidine (17.27 g: 30.64 mmole). Total yield of Steps 4 and 5:74%.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:34])(=[O:33])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39].[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([N:28]([CH3:40])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:33])(=[O:34])[N:19]=3)=[C:14]([OH:35])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:36][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:39]
Reactant: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(N(C)S(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
N-{3-[(1R,2S,7R,8S)-3-(4-Fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 15, 92 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (44 mg, 0.32 mmol) and iodomethane (0.011 mL, 0.18 mmol) were added sequentially. The reaction was stirred at 25° C. for 18 h. The reaction was quenched via the addition of 1.0 M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (91 mg, 0.15 mmol, 96%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.18-2.85 (9H, m), 2.90 (3H, s), 2.97 (3H, s), 3.38 (3H, s), 3.45-3.47 (1H, m), 5.17-5.21 (2H, m), 6.96-7.08 (3H, m), 7.72-8.02 (3H, m). LC-MS (ESI) calcd for C27H29FN4O6S2 588.67, found 589.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[OH:44][CH:45]1[CH2:48][NH:47][CH2:46]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([OH:26])([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)[C:27]3[CH:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[CH:8]=2)[N:3]=[C:2]([N:47]2[CH2:48][CH:45]([OH:44])[CH2:46]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CC(O)C3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), 3-hydroxyazetidine hydrochloride (189 mg, 1.64 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The reaction solution was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H27ClF3N7O2, 645.2. m/z found, 646.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.5, 0.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2, 2.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.57 (dd, J=8.8, 2.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.50-6.46 (m, 1H), 6.35 (s, 1H), 4.55-4.49 (m, 1H), 4.39-4.34 (m, 2H), 4.34 (s, 2H), 3.99-3.93 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.ClC1C(C#N)=CC(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1.C(N)C(C)C.C[Mg+].[Br-].[C:61](Cl)(=[O:64])[CH2:62][CH3:63]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:61](=[O:64])[CH2:62][CH3:63])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Mg+]
Agent: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Br-]
Solvent: CC(C)CN
Product: CCC(=O)N(CC(C)C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
To 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-(isobutylamino)pyridine-3-carbonitrile [prepared by reacting the product of Example 1 step C with isobutyl amine] (0.26 g) in TH (2.5 mL) was added MeMgBr (0.47 mL, 1.4 M solution in toluene THF 3:1) followed by propionyl chloride. After 1 hour 45 minutes the reaction was quenched with 2 M aqueous HCl, diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The dried solution (Na2SO4) was concentrated and purified via flash chromatography on silica gel eluted with 20% EtOAc in hexane affording the title compound. HPLC/MS: 486.2(M+1), 488.2 (M+3); Rt=4.60 min.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[OH:34][CH:35]1[C@H:40]2[CH2:41][NH:42][CH2:43][C@@H:36]1[CH2:37][N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:42]5[CH2:41][C@H:40]6[CH:35]([OH:34])[C@H:36]([CH2:37][N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]6)[CH2:43]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@@H](C1)C2O
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H](C4)C5O)cn3)nc2n1C1CCCCCC1
Yield: 83 %

Procedure:
Following general amide formation method 1, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl 9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave (1R,5S)-tert-butyl 7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (170 mg) in 83% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (s, 1H), 8.67 (d, J=8.59 Hz, 1H), 8.42 (s, 1H), 8.31 (br s, 1H), 7.92 (d, J=8.08 Hz, 1H), 6.46 (s, 1H), 4.74-3.40 (m, 7H), 3.22-2.94 (m, 7H), 2.65 (m, 2H), 2.16-1.54 (m, 13H), 1.49 (s, 9H); LCMS m/z 647.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1.[CH3:19][NH:20][CH2:21][C@H:22]([OH:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.Cl.CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[OH:30][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[CH2:21][N:20]([CH3:19])[C:15]([C:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:8][C:3]([N:2]([CH3:1])[CH3:18])=[N:4][CH:5]=1)=[O:17]
Reactant: CNC[C@H](O)c1cccc(O)c1
Reactant: CN(C)c1ncc(C(=O)O)c(-c2ccccc2)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(CC(O)c1cccc(O)c1)C(=O)c1cnc(N(C)C)nc1-c1ccccc1
Reaction time: 0.08 h
Yield: 18.3 %

Procedure:
2-Dimethylamino-4-phenylpyrimidine-5-carboxylic acid (1.22 g, 5 mmol) is dissolved in tetrahydrofuran (60 ml). After 5 minutes of stirring to the solution are added: L-phenylephrine hydrochloride (1.22 g, 6 mmol) in tetrahydrofuran (50 ml), after another 5 minutes of stirring the N-methylmorpholine (1.21 g, 12 mmol) and after 2 minutes of stirring the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.66 g, 6 mmol). The reaction mixture is stirred for 2 hours at room temperature, then heated at reflux temperature for 2 hours. The solvent is removed in vacuum. To the residue water (50 ml) is added, and the mixture is extracted with chloroform (75 ml), the extract is washed with 10% sodium carbonate solution (35 ml), with water (35 ml), dried over sodium sulphate and evaporated. The residue is chromatographed on silicagel using chloroform-methanol 100/1-100/5 mixture eluent. 0.36 g of the title compound is obtained, m.p.: 79-81° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1
Yield: 100.4 %

Procedure:
Anisole (1.16 g), 6-bromohexanoyl chloride (2.3 g) and aluminum chloride (1.5 g) were reacted and treated in the same manner as in Preparation Example 105 to give 3.07 g of 6-bromo-1-(4-methoxyphenyl)-1-hexanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[I:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(Cl)Cl.CO>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:3]([I:10])[CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(CO)cc1I
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-iodophenyl)methanol (5.97 g) and diethyl ethoxymethylenemalonate (5.34 mL) is heated at 100° C. for 30 min. The reaction is cooled to room temperature. The resulting solid is dissolved in a mixture of CH2Cl2 and MeOH, adsorbed onto silica and chromatographed (Biotage flash 40M, eluant CH2Cl2, then 0.5% MeOH/CH2Cl2). Product containing fractions are combined and condensed to afford diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate as a white solid, m.p. 152-154° C.