Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]([CH3:44])([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:44][C:37]([NH:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:28])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:11]=2)[N:35]=1)([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Reactant: CCC(C)(Nc1ccnc(Cl)n1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C)(Nc1ccnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)n1)C(=O)OC
Temperature: 90 °C
Yield: 161.8 %

Procedure:
A 500 mL pressure vessel was charged with 80 mL DME, 1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (4.4 g, 11.05 mmol), methyl 2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate, (2.44 g, 10.05 mmol), sodium carbonate (10 mL of 2M aq solution, 20 mmol) and degassed the mixture with a nitrogen stream for 30 min. Then, Pd(dppf)Cl2 was added, the flask sealed and heated to 90° C. for 15 hours. The mixture was cooled and filtered through Florisil. Evaporation under vacuum gave 7.8 g of a brown residue which was purified by flash chromatography, (0-80% ethyl acetate-hexane affording 3.9 g (81%) methyl 2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate. 1H NMR (CDCl3) 8.83 (dd, 1H), 8.52 (s, 1H), 8.44 (dd, 1H), 7.28 (dd, 4H), 6.27 (d, 1H), 5.29 (s, 1H), 3.74 (d, 3H), 2.38 (s, 3H), 2.34-2.15 (m, 1H), 2.18-2.00 (m, 2H), 1.98 (s, 2H), 1.74 (s, 3H), 1.34-1.17 (m, 15H), 1.03 (m, 3H). m/e m+1 480.25
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][NH:20][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][N:19]([CH3:24])[N:18]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ccc3cc(-c4c[nH]nn4)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1ncc(-c2ccc3c(ccn3-c3ccc(F)cc3)c2)n1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-triazol-4-yl-1H-indole (6.0 g), iodomethane (6.7 mL), potassium carbonate (6.0 g) and acetone (100 mL) was boiled under weak reflux for 18 hours. The reaction mixture was filtered and the volatile solvents evaporated in vacuo. The mixture of 1-methyl- and 2-methyl-substituted triazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:1). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltriazol-4-yl)-1H-indole (20a) as an oil: (2.1 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.40-7.55 (m, 3H), 7.65 (broad d, 1H), 7.85 (s, 1H), 8.10 (broad s, 1H). Evaporation of the slowest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(1-methyltriazol-4-yl)-1H-indole (20b) as an oil (0.8 g): 1H NMR (CDCl3) δ 4.15 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.50 (dd, 2H), 7.55 (d, 1H), 7.70 (broad d, 1H), 7.75 (s, 1H), 8.10 (broad s, 1H).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(CCCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.26 g), 1-bromo-3-(4-methoxyphenyl)propane (0.23 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The dichloromethane extracts were combined, dried (MgSO4) and concentrated in vacuo to give a solid which was recrystallised from ethanol to give the title compound, yield 0.19 g, m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:38][CH2:39][C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CCN(Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-({4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]benzyl}amino)phenyl]propanoate (0.450 g, 0.720 mmol) in a mixture of ethanol (6 mL) and tetrahydrofuran (15 mL) was added 1 N sodium hydroxide (4.32 mL, 4.32 mmol), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give the title compound (0.274 g, yield 64%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 54 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a N,N-dimethylformamide (125 mL) solution of 4-bromobenzyl alcohol (25 g, 130 mmol) was added potassium tert-butoxide (15.8 g, 141 mmol) at room temperature, which was stirred at 54° C. for 10 minutes. To the reaction solution was added 2-fluoropyridine (15 mL, 154 mmol) was added at a temperature from 40° C. to 58° C., which was stirred at 65° C. for 30 minutes. The reaction solution was cooled to room temperature, and partitioned into water and ethyl acetate. The water layer was further extracted with ethyl acetate (twice). The ethyl acetate layers were combined, washed with water (3 times) and aqueous sodium chloride (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. To the residue was added diethyl ether, which was then concentrated under a reduced pressure to obtain the title compound (34 g) as a crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)[NH:10][CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>CN(C)C=O.O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([CH:9]([NH:10][CH3:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)=[CH:3][CH:4]=2)[NH:13][CH:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cnn(C)c3)cc2)NC)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-N-methylethanamine (157 mg, 0.43 mmol), sodium carbonate (138 mg, 1.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.86 mmol) in N,N-dimethylformamide/water (2:1) (9 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 366.
Reaction SMILES: [OH:1][C@@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][O:1][C@@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CI
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
Cool a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][S:23][C:17]=2[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[S:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1Cc2sccc2CN1
Product: CC1Cc2sccc2CN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 51 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[C:19]([CH3:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[C:19]([CH3:25])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Cl)cccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 40.9 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-chloro-2-methylphenol (26 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-chloro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (15 mg, 41%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.00 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.55-7.65 (m, 3H), 7.16 (d, J=8.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 5.22 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:27])=[C:24]([F:26])[F:25]>CN(C)C=O>[F:27][C:23](=[C:24]([F:26])[F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)=C(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 26.2 %

Procedure:
Using 0.50 g of (4-(trifluoromethoxy)benzyl)malononitrile, 9 ml of N,N-dimethylformamide, 96 mg of sodium hydride (60% in oil), and 0.79 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.19 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (49)).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])(=[O:15])=[O:14].Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Product: CS(=O)(=O)c1ccccc1Nc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH:27][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:8][CH:9]=3)=[O:14])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1csc(-c2ccccc2)n1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-thiazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-phenyl-thiazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H18N4O2S (m/e) 366, obsd 367 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH:12](Br)([CH3:14])[CH3:13].P([O-])([O-])([O-])=O>CN(C=O)C>[CH:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Br
Reactant: OCc1ccc(O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CO)cc1
Reaction time: 18 h
Yield: 69.6 %

Procedure:
4-Hydroxybenzylalcohol (1 g) in DMF (10 ml) under nitrogen at 0° C. was treated portionwise with sodium hydride (355 mg). The resulting solution was stirred for 0.5 h before isopropyl bromide (0.99 g) was added, and the solution was stirred for a further 18 h. Phosphate buffer (pH=6.5) was then added and the solution was extracted with EtOAc. The combined organic layers were then washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 90 g) eluting with 40-60° C. petroleum ether-EtOAc (4:1) to give the title compound (931 mg). LCMS RT=2.51 min.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([C:14]2(O)[CH:19]3[CH2:20][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:14]1([C:9]2[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:13][CH:12]=[CH:11][N:10]=2)[CH:19]2[CH2:20][N:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: CCCCCCOc1nccnc1C1(O)CN2CCC1C2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCOc1nccnc1C1(Cl)CN2CCC1C2

Procedure:
A mixture of 4.8 g of (26) (0.021 mol) and 125 ml of hexanol that had reacted with 1.5 g of Na (0.065 mol) was heated to 80° C. for 45 min. The reaction was cooled to ambient, 100 ml of 1N HCl was added, and the hexanol was azeotroped off with water. The residue was made basic with 1N NaOH and extracted 3× with 50 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark solid. Recrystallization of the solid from ether gave 3.83 g of 3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (26a) as a floculent yellow solid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.65 (7H, m), 1.85 (2H, m), 2.25-3.07 (6H, m), 3.1 (1H, d), 3.75 (2H, d), 4.45 (2H, t), 8.01 (1H, d), 8.07 (1H, d). A solution of 1.5 g of (26a) (0.0052 mol) in 75 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1.5 h the reaction was heated to reflux for 45 min. The reaction was cooled to ambient, water was added, and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2 the washed with brine, dried, and the solvent evaporated to give a yellow oil. Radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 gave 1.2 g 3-chloro-3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptane (26b) as a pinkish liquid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.95 (10H, m), 2.25-3.9 (7H, m), 4.4 (2H, t), 8.0-8.1 (2H, m). A mixture of 1.2 g of (26b) (0.0039 mol) and 0.5 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi H2. The catalyst was removed, the solvent evaporated, the residue suspended in water, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. Tlc shows two major spots, 10% ethanol-1% NH4OH-CHCl3. The less polar of the two component was not well separated. The more polar component was treated with HCl in isopropanol and thoroughly evaporated. The residue was recrystallized from ether to give 0.15 g of (27) as slightly hygroscopic colorless crystals, mp 117°-118° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.55 (8H, m), 1.85 (3H, m), 3.2-3.75 (6H, m), 4.05 (2H, m), 4.38 (2H, m), 8.05 (1H, d), 8.08 (1H, d). Anal. C16H25N3O-HCl-0.5H2O requires C: 59.89; H: 8.48; N: 13.10%. Found C: 59.83; H: 8.31; N: 12.95%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][CH3:26])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)#[N:28]>O1CCCC1.C(O)(=O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:7]1[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]3[N:25]([CH3:26])[C:36]([CH2:35][C:32]4[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][CH:33]=4)=[N:1][C:2]=3[CH:3]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c(N)c1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C

Procedure:
Prepared analogously to Example 24f from ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-yl]-propionate, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran, glacial acetic acid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][NH:12][C:11](=O)[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][NH:12][C:11](=[S:40])[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2OC(F)(F)F)[C@H](Cc2ccccc2)CCCN1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1OC(F)(F)F)N1CC(=S)NCCC[C@H]1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
A solution of compound 31m (500 mg, 1.13 mmol) in toluene (30 mL) was treated with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (457 mg, 1.13 mmol), heated at 80° C. for 30 min, cooled to rt, treated with NaHCO3 (95 mg, 1.13 mmol) and stirred for 10 min. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=4:1) to give compound 31n (491 mg, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](ON1C(=O)CCC1=O)=[O:15])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:9]=[CH:8]2.[NH2:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39])=[O:15])[N:10]([CH2:24][CH:25]([CH3:26])[CH3:27])[N:9]=[CH:8]2
Reactant: N[C@H]1CCNC1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (700 mg, 1.58 mmol) in dichloromethane (5 mL) was added (S)-3-aminopyrrolidin-2-one (prepared according to Example 2, 205 mg, 2.05 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 25-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ia) (520 mg, 77%). Mass spec: 429 (M+1). 1H NMR (CDCl3) δ 8.37 (s, 1H), 8.26 (d, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.03 (br, 1H), 4.59 (ddd, 1H), 4.22 (d, 2H), 3.46 (m, 2H), 2.87 (m, 1H), 2.36 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H).