Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=[CH:6]1)[CH3:2].C([Li])CCC.CON(C)[C:27](=[O:29])[CH3:28].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:12]([CH2:13][CH3:14])([CH2:17][CH3:18])[CH2:15][CH3:16])[N:7]=[C:6]1[C:27](=[O:29])[CH3:28])[CH3:2]
Reactant: CON(C)C(C)=O
Reactant: CCOCn1cnc(CO[Si](CC)(CC)CC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCn1cc(CO[Si](CC)(CC)CC)nc1C(C)=O
Temperature: -78 °C
Reaction time: 17 h

Procedure:
The compound (665 mg) obtained in (3) was dissolved in THF (20 mL), and cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.69 M hexane solution, 1.50 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (0.50 mL) was added using a syringe, and stirring was continued for 17 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→30%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (520 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[C:28]4[S:24][C:25](=[O:30])[NH:26][C:27]4=[O:29])=[CH:18][CH:17]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(-c2cccc(Oc3ccc(C=O)cc3)c2)cc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)c2)cc1
Yield: 77.5 %

Procedure:
A mixture of 57 (1.23 g, 4.0 mmol), 2,4-thiazolidinedione (0.48 g, 4.0 mmol), benzoic acid (0.60 g, 4.8 mmol) and piperidine (0.61 mL, 6.0 mmol) in toluene (30 mL) was heated to a vigorous reflux until most of the solvent had evaporated. A yellow suspension was achieved by addition of acetic acid (25 mL) followed by sonication. Filtration of the suspension followed by washing with acetic acid (10 mL) yielded 58 (1.25 g, 75%) after filtration and oven drying. 1H NMR (400 MHz, DMSO-d6): δ 12.57 (br s, 1H), 7.78 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.49 (d, J=5.2 Hz, 2H), 7.36 (t, J=1.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 3.7 (s, 3H).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:22]1[CH:29]2[CH:23]1[CH2:24][CH2:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=12.C[Si](C)(C)[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[O:36]=[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]1[C@@H:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25][CH2:24][C@H:23]1[OH:22]
Reactant: c1ccc2c(c1)OCCC1OC21
Reactant: C[Si](C)(C)Oc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=c1ccccn1[C@@H]1c2ccccc2OCC[C@H]1O
Temperature: 0 °C

Procedure:
6.40 g (20 mmol) of tetrabutylammonium fluoride trihydrate are added to a mixture of 3.24 g (20 mmol) of 4,5-epoxy-2,3,4,5-tetrahydro-1-benzoxepin and 10 g (60 mmol) of 2-trimethylsilyoxy-pyridine, and the mixture is heated at 80°-90° C. with stirring. After a reaction time of 5 hours, the mixture is slowly stirred into ice-water, and the precipitated solid is filtered off with suction and recrystallized from methanol with the addition of small amounts of dioxane. Crystals of melting point 232°-234° C. are obtained.
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:31]1[CH2:36]CN(CC2CCCCCC2)C[CH2:32]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:26])[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[OH:15])[CH2:10][CH2:11]2)[CH2:36][CH2:31][CH2:32][CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccco2)C2CCCC2)CC1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccco1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-(2-furyl)-2-hydroxyacetic acid obtained in Example 50 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].Cl[C:22]([O:24][CH2:25][CH2:26]Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:26][CH2:25][O:24][C:22]1=[O:23]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Reactant: O=C(Cl)OCCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2CCOC2=O)C1
Yield: 108.6 %

Procedure:
Analogously to example 45a), (R)-2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)phenylamine (300 mg, enantiomer B, preparation as described in WO2004085404) was reacted with 2-chloroethyl chloroformate (140 mg). 400 mg of the desired product were obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[C:13]([O:23][CH3:24])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O>>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH:14]([C:13]([O:23][CH3:24])=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH:14]([C:13]([O:23][CH3:24])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: COC(=O)C(O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Product: COC(=O)C(OC(=O)c1ccc(C(=O)OC(C(=O)OC)c2ccccc2)nc1)c1ccccc1

Procedure:
Analogously to Example 1, 10 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride and this is reacted with 19.9 g of methyl (±)-mandelate. After extraction, working up is carried out by chromatography over silica gel with a mixture of toluene and ethyl acetate as the mobile phase.
Reaction SMILES: C(N(CC)CC)C.N1(O)C2C=CC=CC=2N=N1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([OH:30])=O)=[CH:21][CH:20]=1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([CH3:35])([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([NH:43][O:42][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)=[O:30])=[CH:23][CH:24]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Yield: 76.5 %

Procedure:
Triethylamine (5.49 g, 54.3 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (7.5 g, 49 mmol) were added to a solution of the (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (9.1 g, 27.1 mmol) in dichloromethane (100 mL). After 10 minutes O-tetrahydro-2H-pyran-2yl-hydroxylamine (4.6 g, 39 mmol) was added followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (7.2 g, 38 mmol). After 12 h the reaction was quenched by the addition of saturated aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 7:3-6:4) afforded the title compound as a white solid (9.0 g, 76%). LCMS m/z 434.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.90 Hz, 6H) 1.69 (br. s., 3H) 1.78-2.06 (m, 1H) 2.27-2.55 (m, 2H) 2.59-2.72 (m, 1H) 3.03 (d, J=6.64 Hz, 3H) 3.50 (d, J=11.32 Hz, 1H) 3.95-4.22 (m, 1H) 4.97 (d, J=9.37 Hz, 1H) 7.22 (dd, J=8.39, 4.49 Hz, 2H) 7.49 (d, J=8.20 Hz, 2H) 11.36 (br. s., 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]3[N:22]([C:24]([CH3:27])=[N:25][N:26]=3)[CH:23]=2)=[CH:4][CH:3]=1.I[CH:30]1[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[NH:32]1[CH2:33][CH:30]([N:12]2[C:11]3[C:10](=[O:17])[N:9]([C:18]4[CH:19]=[C:20]([CH3:28])[C:21]5[N:22]([C:24]([CH3:27])=[N:25][N:26]=5)[CH:23]=4)[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]=3[C:14]([CH3:16])=[N:13]2)[CH2:31]1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared using an analogous procedure to that described in Example 134 using 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (750 mg, 1.909 mmol) and stirring the reaction mixture for 30 min at 80° C. after addition of tert-butyl 3-iodoazetidine-1-carboxylate. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) followed by preparative HPLC (Gilson gx-281. Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient: 5% to 60% B in 20 min; A=0.1% TFA in H2O, B=CH3CN. Detection: UV) to afford:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH:29]([NH:32][CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH:29]([N:32]([CH:33]([CH3:35])[CH3:34])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:16][CH:15]=1)([CH3:31])[CH3:30]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(2-methylphenyl)benzoic acid (4.00 g, 18.8 mmol) in DCM (150 mL) was added oxalyl chloride (10.00 g, 78.8 mmol) followed by 5 drops of DMF. The reaction mixture was stirred at RT for 3 h until a clear solution resulted. The solvent was removed in vacuo. The residue was dissolved with DCM (100 mL) and treated with aq. potassium carbonate (3.41 mL, 56.5 mmol). The reaction mixture was cooled to 0° C., and a solution of diisopropylamine (5.33 mL, 37.7 mmol) in DCM (50 mL) was added dropwise. The resulting mixture was stirred at RT over 12 h. The resulting mixture was quenched by the slow addition of saturated aqueous Na2CO3 (100 mL). The organic phase was separated and aqueous phase was extracted with dichloromethane (3×60 mL). The combined organic phases were washed with brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give N,N-diisopropyl 4-(2-methylphenyl)benzamide as an off-white solid. MS (ESI, pos.ion) m/z: 296 (M+1)
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17](=O)[CH2:18][Cl:19])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>ClCCCl>[F:1][C:2]1[C:15]([N:16]=[C:17]([Cl:41])[CH2:18][Cl:19])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)CCl)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: C#CCN1C(=O)COc2cc(F)c(N=C(Cl)CCl)cc21
Reaction time: 2 h

Procedure:
First, 1.00 g of N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-2-chloroacetamide, 2.25 g of triphenylphosphine polymer bound and 4 ml of carbon tetrachloride were dissolved in 35 ml of 1,2-dichloroethane, and then the reflux under heat was continued for 2 hr. After letting the solution stand to cool the same, the solid was filtered out, and then the solvent was distilled out under reduced pressure to quantitatively obtain N-(7-fluoro-4-propargyl-2H-1,4-benzoxazine-3(4H)-one-6-yl)-2-chloroacetimidoylchloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (6.0 g) described in Preparation Example 109 and pyrrolidin-2-one (1.3 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.80 g) was obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:9][C:8]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1)=[O:10]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (31 ml) and acetyl chloride (15 ml) were added dropwise to a chloroform (100 ml) solution of 4-fluoroaniline (22.3 g) in this order under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The thus-obtained solid was washed with water, collected by filtration, and recrystallized from ethanol-water to obtain colorless crystals of 4-fluoroacetanilide (25.5 g; yield, 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][C:30]4[C:25]([CH:24]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: OB(O)c1cnc2ccccc2c1
Product: COc1cccc(Nc2nc(-c3cnc4ccccc4c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with quinoline-3-boronic acid using General Procedure A. Purification on silica yielded 117. NMR: (CDCl3): 3.90 (s, 3H, CH3), 4.17 (s, 3H, CH3), 6.90 (dd, H, ArH, J=2.4, 8.32), 7.20 (d, H, ArH, J=7.92), 7.35 (d, H, ArH, J=11.36), 7.41 (t, H, ArH, J=8.11), 7.51 (s, H, NH), 7.62 (t, H, ArH, J=7.51), 7.79 (t, H, ArH, J=6.970, 8.00 (d, H, ArH, J=8.12), 8.20 (d, H, ArH, J=8.43), 9.30 (d, H, ArH, J=1.8), 10.07 (d, H, ArH, J=2.09). MS: (ESI+) MH+=383.23
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CN(C)CCNN
Product: CN(C)CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=6.2 Hz, 2 H), 8.22 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.7 Hz, 1H), 7.85 (m, 2 H), 7.73 (m 2H), 7.57 (t, J=7.1 Hz, 1H), 7.23 (m, 2H), 7.17 (d, J=9.1 Hz, 2H) 7.00 (d, J=6.2 Hz, 2H), 5.42 (s, 2H), 4.05 (t, J=6.6 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H), 2.10 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:19][C:18]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=3[Br:16])[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1ccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c(Br)c1
Temperature: 195 °C
Yield: 4 %

Procedure:
To a solution of 4-(4-hydroxyanilino)-6-chloropyrimidine (Reference Example 5, 5 g) was added 2-bromo-4-methylaniline (7.5 ml) and the reaction mixture was heated at 195° C. for 24 hours. The residue was absorbed onto silica and purified by column chromatography eluting with DCM:MeOH (19:1) to give the title compound (336 mg, 4%). NMR: 2.28 (3H, s), 5.72 (1H, s), 6.68 (2H, d), 7.17 (3H, m), 7.39 (1H, d), 7.48 (1H, s), 8.05 (1H, s), 8.38 (1H, s), 8.65 (1H, s), 9.08 (1H, s); m/z 371 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH2:18](Cl)Cl.F[B-](F)(F)F.[H+].C[Si](C=[N+]=[N-])(C)C>CCOC(C)=O.CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:18])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: ClCCl
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CO[C@H](C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 31 %

Procedure:
To a round bottom flask was added (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (364 mg, 1.31 mmol) followed by the addition of DCM (10.8 mL). The reaction mixture was then cooled to 0° C. in a (ice/water bath) under nitrogen. To this cold solution was added tetrafluoroboric acid (0.20 mL, 1.31 mmol, 50% aqueous solution) followed by the addition of trimethylsilyldiazomethane (1.96 mL, 3.93 mmol, 2 M in hexanes) divided into 3 portions added 20 min apart. A second addition of trimethylsilyldiazomethane in hexanes (1.96 mL, 3.93 mmol, 2 M in hexanes) again divided into 3 portions added 20 min apart was added. Reaction mixture was quenched with water and diluted with DCM. Phases paritioned and the aqueous phase extracted with DCM. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (119 mg, 0.41 mmol, 31% yield) as a colorless oil which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) δ 1.09 (d, J=6.50 Hz, 3H) 3.44 (s, 3H) 4.09 (qd, J=6.46, 4.16 Hz, 1H) 4.38-4.49 (m, 1H) 4.60 (dd, J=9.49, 2.84 Hz, 1H) 4.99 (ddd, J=8.50, 3.95, 2.96 Hz, 1H) 8.23 (s, 1H). LCMS m/z 292.0 (M+H)+, Rt 0.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][O:10][C@:8]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(O)c2cccc(Cl)c2)C1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (2.5463 g, 7.49 mmol), 60% NaH (2.120 g, 53 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (7.820 g, 32.7 mmol) in THF was heated at 80° C. for 25 h and then cooled to rt. The reaction mixture was then quenched with water and extracted with ethyl acetate (3×), dried over Na2SO4. After the solvent was evaporated under reduced pressure, crude (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:14]=2)[CH:4]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[CH:31]1([NH:37][C:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:14]=3)[N:6]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NC2CCCCC2)n1

Procedure:
A solution of EXAMPLE 1B (6.7 g, 15.1 mmol) and cyclohexanamine (6.90 mL, 60.3 mmol) in dioxane (165 mL) was heated at 100° C. overnight. The mixture was concentrated to afford the crude title compound which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]12[CH2:12][C:6]3(CO)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Br:1][C:2]12[CH2:12][C:6]3([N:16]4[CH:20]=[CH:19][CH:18]=[N:17]4)[CH2:5][C:4]([CH3:15])([CH2:10][C:8]([CH3:11])([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: CC12CC3(C)CC(Br)(C1)CC(CO)(C2)C3
Reactant: c1cn[nH]c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC12CC3(C)CC(Br)(C1)CC(n1cccn1)(C2)C3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of the 5-bromo-3,7-dimethyltricyclo[3.3.1.13,7]dec-1-ylmethanol (8.0 g, 29.3 mmol) in toluene (60 mL) was added 1H-pyrazole (1.55 g, 22.7 mmol) and cyanomethylenetributylphosphorane (2.0 g, 29.3 mmol) under nitrogen. After the addition, the mixture was stirred at 90° C. overnight. The reaction mixture was then concentrated, and the residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH3:19]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]([NH:20][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[O:14])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCC(N)CC
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Product: CCOc1ccc(C=CC(=O)NC(CC)CC)cc1

Procedure:
Prepared in a similar manner to example 4 using 3-(4-ethoxy-phenyl)-acrylic acid and 3-pentylamine. MS (M+H, 262.2).