Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][N:13]1[CH2:16][CH2:15][CH2:14]1)(=O)=O>CN(C=O)C>[N:1]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OC(CCN1CCC1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CCN1CCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.4 1.50 g (23.1 mmol) of sodium azide are added to a solution of 2.00 g (7.43 mmol) of 3-azetidin-1-yl-1-phenylpropyl methanesulfonate in 50 ml of DMF, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed on a silica-gel column with ethyl acetate/methanol as eluent: 1-(3-azido-3-phenyl-propyl)azetidine as colourless viscous oil; HPLC/MS 0.9 min; [M+H] 217.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:6]#[N:7].[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:11][C:15](=[O:16])[CH2:14][O:13][CH3:12])[CH:10]=1)[C:6]#[N:7])=[O:16]
Reactant: N#Cc1cc(N)cc(N)c1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(C#N)cc(NC(=O)COC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-diaminobenzonitrile monohydrochloride (5.1 g) in pyridine (100 ml) is added dropwise methoxyacetyl chloride (6.0 ml) at room temperature. The mixture is stirred at room temperature for 2 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with water and then with aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting solid substance is recrystallized from ethyl acetate-n-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:30][C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:24])=[C:16]2[N:15]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: Cc1cccnc1N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1cccnc1NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a suspension of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 25.0 mg, 0.072 mmol) in CCl4 (1.0 mL) was added thionyl chloride (0.10 mL) and the mixture heated at reflux for 4 hours. The mixture was cooled to ambient temperature and was concentrated to a brittle foam. The foam was dissolved in pyridine (2 mL), 2-amino-3-methyl-pyridine (9.3 mg, 0.086 mmol) was added and the mixture was heated at 90° C. for 20 hours. The reaction was cooled to ambient temperature and the pyridine evaporated. The residue was partitioned into 1M NaOH and EtOAc, mixed and the EtOAc layer removed. The aqueous layer was extracted with EtOAc and combined EtOAc fractions were washed with H2O, saturated NaCl and dried over MgSO4. The solution was filtered and concentrated, and the resulting solid was washed with dry Et2O to afford the title compound as a white solid (7 mg, 29%). MS (apci) m/z=435.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 634.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:15][CH:16]1[CH2:33][N:21]2[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:32]=[C:20]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>ClCCl>[Si:8]([O:15][CH:16]1[CH2:33][N:21]2[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:32]=[C:20]2[CH2:19][NH:18][CH2:17]1)([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1Cc2nc3cnc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CNCc2nc3cnc4ccccc4c3n2C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Trifluoroacetic acid (500 mL of a 10% solution in dichloromethane) was added to tert-butyl 11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (9.23 g, 19.7 mmol), and the reaction was stirred at ambient temperature for 75 minutes. The solvent was removed under reduced pressure, and the residue was shaken with triethylamine (300 mL) and dichloromethane. The solution was concentrated under reduced pressure, and the product was dried under high vacuum for two hours to provide 11-{[tert-butyl(dimethyl)silyl]oxy}-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline, which was used in the next step without removing the triethylamine trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)=[O:12])[CH:3]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)=[O:12])[CH:3]=1
Reactant: Nc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1N

Procedure:
Prepared analogously to example 83d by hydrogenation of 4-amino-5-nitro-N-(4-trifluoromethyl-pyridin-2-yl)-picolinamide using palladium/charcoal 10% in methanol and THF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:37])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (100 mg, 0.25 mmol) and Lawesson's Reagent (122 mg, 0.30 mmol) were dissolved in dioxane (10 mL) under nitrogen. The reaction is heated to 100° C. for 20 minutes then cooled to ambient and evaporated. The residue is partitioned between ethyl acetate (150 mL) and water (50 mL). The organic phase is washed 3 times with water (50 mL) and brine (50 mL), then dried over MgSO4, filtered and evaporated to a nearly colorless glass. The product is purified by radial chromatography over silica gel, eluting with 0-10% methanol-methylene chloride to give a white solid foam (89 mg, 85%). MP=95-98° C., decomposes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:38]#[N:39].CO>CN(C=O)C>[C:38]([NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1)#[N:39]
Reactant: N#CBr
Reactant: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-({1-[4-(6-amino-pyridin-2-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (120 mg, 0.25 mmol) in DMF (2 mL) was treated with NaH (95%, 10 mg, 0.40 mmol) at 0° C. The reaction was stirred for 20 min. and BrCN (Aldrich, 32 mg, 0.30 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜0.2 mL) was added to quenched extra NaH. The reaction solution was partitioned between DCM and water. The aqueous layer was extracted with a chloroform/IPA “cocktail” (3:1 v/v). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was purified by silica gel column on a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)=[O:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2C=O)cc1F

Procedure:
To a solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) in THF (80 mL) was added 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) and Na2CO3 (2M, 80 mL) and then was bubbled with nitrogen for 10 minutes. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 hours. The THF layer was separated, filtered through a pad of silica gel, and washed with THF to give 80 mL solution of 4(2′-formylphenyl)-2-fluoroaniline in THF. MS(CI) m/z 233 (M+NH4, 100%). To the filtrate (15 mL from total 80 mL) was added Me2NH.HCl (0.68 g, 8.33 mmol) and the resulting mixture was refluxed for 2 hours. The mixture was cooled to room temperature, and to it was added MeOH (5 mL) and then NaBH4 (0.32 g, 8.33 mmoL). After being stirred at 50° C. for 1 hour, the mixture was cooled to room temperature again and quenched with 1N HCl to pH 1. The aqueous layer was separated, neutralized with 50% NaOH to pH 12, and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated, and purified by silica gel chromatography eluted with EtOAc to give 4-(2′-N,N-dimethylaminomethylphenyl)-2-fluoroaniline (0.89 g, 87.5%). 1H NMR (CDCl3) δ 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.31–7.21 (m, 3H), 7.14 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 3.76 (bs, 2H), 3.34 (s, 2H), 2.17 (s, 6H); 19F NMR (CDCl3) δ −136.19; MS(ES+) m/z 245.2 (M+H, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].[OH-:12].[K+].Cl.[NH2:15]O>Cl>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:15][OH:12])[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: NO
Reactant: CCC(=O)c1ccccc1O
Agent: Cl
Agent: [K+]
Product: CCC(=NO)c1ccccc1O
Reaction time: 4 h

Procedure:
15 g of 1-(2-hydroxyphenyl)-1-propanone are added dropwise to 170 ml of a 40% aqueous solution of potassium hydroxide. To this emulsion are then added, in increments, 31.2 g of hydroxylamine hydrochloride and the mixture is stirred for 4 h at 0°-5° C. The reaction mixture is then acidified with 150 ml of concentrated hydrochloric acid, the precipitated product is isolated by filtration, washed with water and dried, giving 1-(2-hydroxyphenyl)-1-propanone oxime having a melting point of 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:5]=[CH:6][C:7]=1F.BrC1SC(C(OCC)=O)=NC=1C1C=CC=C(Cl)C=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:13]2[S:12][C:11]([C:22]([OH:24])=[O:23])=[N:10][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Agent: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Product: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 5A. 83.0 mg (78% of theory) of the title compound are obtained.
Reaction SMILES: O1CCOCC1.[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]#[N:32])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([Sn]([N:48]=[N+:49]=[N-:50])(CCCC)CCCC)CCC.[OH-].[Na+]>CCOCC>[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([O:29][CH2:30][C:31]4[NH:50][N:49]=[N:48][N:32]=4)=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1c(OCc2nnn[nH]2)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 25 °C

Procedure:
To a 5 ml 1,4-dioxane solution of 300 mg of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile was added 0.8 ml of tributyltin azide, followed by heating under reflux for 2 days. After cooling to room temperature, aqueous 1M sodium hydroxide solution and ether were added, followed by layer separation operation. To the aqueous layer was added 1 M hydrochloric acid, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. By adding ether to the resulting residue and collecting the insoluble materials by filtration, 70 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(1H-tetrazol-5-ylmethoxy)quinolin-4(1H)-one was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=C[C:11]=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.NC1N=CC=C(C)N=1.[CH:57]1([CH2:63][C@@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67][C:68]2S[CH:70]=[CH:71][N:72]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([CH2:63][C@H:64]([N:73]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[C:74]2=[O:82])[C:65]([NH:67][C:68]2[CH:11]=[CH:12][N:8]=[C:71]([CH3:70])[N:72]=2)=[O:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccnc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: Cc1nccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)n1
Yield: 65 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 150 mg; 0.52 mmol) and 2-amino-6-methylpyrimidine (57 mg; 0.52 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 65% ethyl acetate/hexanes) 109 mg of (S)-3-Cyclohexyl-N-(2-methyl-pyrimidin-4-yl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white foam: EI-HRMS m/e calcd for C22H26N4O2 (M+) 378.2056, found 378.2054.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[C:32]([NH:33][C:34](=[O:36])[CH3:35])[C:27]([O:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(C)=O
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1NC(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (synthesized in a similar manner as Stage 64.1.1, (HPLC: tR 1.84 min (Method A); M+H=293 MS-ES)) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.37 (s, 1H), 8.96 (s, 1H), 8.45-8.43 (m, 1H), 8.12-8.08 (m, 2H), 8.01-8.00 (m, 1H), 7.85-7.82 (m, 1H), 7.52-7.50 (m, 1H), 4.44 (q, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 2.15 (s, 31-1), 1.92 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:10]([CH2:11]O)=[CH:9][N:8]=[C:7]([C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[N:6]=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:11][C:10]1[C:5]([CH2:4][CH2:3][O:2][CH3:1])=[N:6][C:7]([C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[N:8][CH:9]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
A cooled (0° C.) solution of 0.94 g (3 mmol) of [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol in 30 ml dichloromethane was treated with 0.44 ml (6 mmol) thionylchloride and stirred for 2.5 h at RT. The reaction was evaporated, dissolved twice in heptane an evaporated to give 1.0 g of pure 5-chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine.
Reaction SMILES: [C:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:26])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=S)c1ccc([N+](=O)[O-])cc1
Yield: 68 %

Procedure:
The preparation of Example 1 was repeated with the changes that N-tert-butyl 4-nitrobenzamide (3.00 g, 0.0135 mole) and 2,4-bis (4-methoxyphenyl) -1,3 -dithia-2,4-diphosphetane-2,4-disulfide (3.28 g, 0.0081 mole) were the starting reactants and the reaction was carried out by refluxing in 50 mL dry toluene solvent for 3 hours. In addition, the solvent was removed in vacuo leaving a yellow viscous oil. The oil was taken up into ethyl acetate and the solution filtered through silica gel. The solvent was removed in vacuo, the residue taken up into ethanol, and the mixture filtered through fluted filter paper. Recrystallization from ethanol produced 2.20 g golden crystals of the desired product (68% yield), mp 136°-138° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 8.21 ppm (d, 8.0 Hz, 2H; 3,5-aryl H); 7.76 ppm (d, 8.0 Hz, 2H; 2,6-aryl H); 1.67 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:33][CH:34]4[CH2:38][CH2:37][CH2:36][O:35]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NCC1CCCO1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCC1CCCO1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z=530.96 (M+H+); retention time=0.78 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>O1CCCC1>[C:7]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:21][CH3:22])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 14 h
Yield: 87.6 %

Procedure:
To a solution of 2-amino-5-tert-butyl-1,3,4-thiadiazole (Aldrich) (2.5 g, 16.3 mmol) in tetrahydrofuran (30 mL) were added 5-chloro-2-methoxybenzoic acid (Aldrich) (3.65 g, 19.6 mmol), triethylamine (5.5 mL, 39.5 mmol), and 1-propanephosphonic acid cyclic anhydride 50% solution in ethyl acetate (Aldrich) (11.6 mL, 19.6 mmol). The reaction mixture was stirred at about room temperature for 14 hours, cooled with external ice bath while quenching with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.65 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43 (s, 9H), 3.88 (s, 3H), 7.22 (d, J=8.7 Hz, 1H), 7.55-7.64 (m, 2H), 12.41 (s, 1H); MS (ESI+) m/z 326 (M+H)+.