Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=O)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C[N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([NH2:19])=[O:17])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CCNc1nc(Cl)cc2nccnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanoic acid (2.22 mmol), HATU (2.66 mmol), DIPEA (6.65 mmol) and NH4Cl (4.43 mmol) in THF (10 mL) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was treated with water. The precipitates were collected by filtration and dried to give the title compound. MS (m/z): 252 (M+H)+.
Reaction SMILES: [ClH:1].[Cl-:2].[NH2:3][C:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][P+:8]([CH3:11])([CH3:10])[CH3:9].C(O[Cl:19])(C)(C)C>CO.O>[Cl-:19].[Cl:1][N:3]([Cl:2])[C:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][P+:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(N)CCC[P+](C)(C)C
Reactant: CC(C)(C)OCl
Reactant: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(CCC[P+](C)(C)C)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of (4-amino-4-methylpentyl)trimethylphosphonium chloride hydrochloride (0.70 g, 2.82 mmol) in a mixture of methanol (20 mL) and water (10 mL) was cooled in an ice bath for 15 min. t-BuOCl (1.0 mL, 3.0 equiv, 8.5 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., then room temperature for 30 min. The methanol was removed under reduced pressure and the aqueous solution was purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/methanol and 0.05% acetic acid as modifier. Fractions were collected using UV absorbance at 215 nm. Fractions were pooled frozen and lyophilized to give a pale yellow solid (0.654 g, 82.6%). 1H NMR (D2O, 400 MHz): δ 1.40 (s, 6H), 1.65-1.69 (m, 2H), 1.85-1.89 (d, J=14.4, 9H), 1.89-1.92 (m, 2H), 2.19-2.27 (m, 2H). LRMS (ESI+) for C9H21Cl2NP+ (244.1); Found: 244, 246 (M+, M2H+)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[C:8]([C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)[CH3:2].C(COC)OC.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:10]=[C:9]2[C:11]([O:16][C:14](=[O:15])[C:8]2=[CH:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOCc1ccc(C(=O)O)c(C(=O)O)n1
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOCc1ccc2c(n1)C(=O)OC2=O

Procedure:
21 g of 6-ethoxymethylpyridine-2,3-dicarboxylic acid are added to a mixture of 100 ml of dimethoxyethane, 28 ml of acetic anhydride and 15 ml of pyridine while stirring and the whole is further stirred for 6 hours at room temperature before being concentrated by evaporation under a high vacuum. 20 g of anhydride remain in the form of an oily liquid with a refractive index nD22 of 1.5480.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[C:14]([Cl:16])[CH:13]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Yield: 88.1 %

Procedure:
To a mixture of 3,5-dichlorobenzohydrazide 5 (0.5 g, 2.4 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 92%) which was used for the next step without further purification. A mixture of 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.52 g). Yield: 88%.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:27]1(OB(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: OB(O)Oc1ccccc1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1ncccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.470 mmol) N-(3-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine acetate, 0.086 g (0.705 mmol) phenylboric acid, 0.149 g (1.411 mmol) sodium carbonate, and 0.038 g (0.033 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 20 hr at 110° C. under a nitrogen atmosphere. However, after this reaction time the starting material/product ratio was still 1:1. Therefore, further heating was performed for 16 hr, and then for an additional 25 hr. After a total reaction time of 61 hr the reaction was terminated due to increasing formation of by-products. After appropriate workup and purification via preparative HPLC, 41 mg pure N-(2,6-dimethoxybenzyl)-N′-(3-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([CH3:1])[CH:3]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(=O)O)ccc1Oc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A mixture of 3-methyl-4-phenoxybenzoic acid (114 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (0.2 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-phenoxybenzamide as a white solid (50 mg, 28%). LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.24 (t, J=4.8 Hz, 1H), 8.83 (s, 1H), 7.68 (dd, J=9.6 Hz, J=2.1 Hz, 1H), 7.41-7.35 (m, 2H), 7.13 (t, J=7.5 Hz, 1H), 6.96-6.93 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 5.80 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1.C(OC(N1CCO[C@@H](C2C=CC(N)=C([Cl:47])C=2)C1)=O)(C)(C)C>>[ClH:2].[Cl:47][C:6]1[CH:7]=[C:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:3]=[CH:4][C:5]=1[NH:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid (described in example 112) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:7]=1[CH3:8])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(OC)cc2)c1C
Yield: 64 %

Procedure:
9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 8.7 grams p-methoxy phenyl-hydrazine-hydrochloride, 4.9 grams anhydrous sodium acetate and 90 milliliters ethanol were mixed and the mixture heated to boiling temperature under reflux for 2.5 hours. The reaction mixture was thereafter evaporated and ether added to the residue. The ether phase was extracted with water and the ether evaporation. The crystalline residue was recrystallized twice from a mixture of ethanol and water. 9.2 grams 3,5-dimethyl-1-(p-methoxy phenyl)-pyrazol-4-acetic acid-ethyl ester, melting at 71°-72° C. were obtained, representing a yield of 64%.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH3:17])=[C:8]2[C:18](O)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([N:29]([CH2:32][CH:33]([OH:36])[CH2:34][NH2:35])[CH2:30][CH3:31])[CH3:28].Cl>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:27]([N:29]([CH2:32][CH:33]([OH:36])[CH2:34][NH:35][C:18]([C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10]([C:9]=1[O:16][CH3:17])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:19])[CH2:30][CH3:31])[CH3:28]
Reactant: COc1c(C(=O)O)n(-c2ccccc2)c2ccccc12
Reactant: CCN(CC)CC(O)CN
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccccc1

Procedure:
6.6 g of N-phenyl-3-methoxyindole-2-carboxylic acid and 7 ml of triethylamine in 75 ml of methylene chloride are added dropwise to 7 g of ethyl chloroformate in 25 ml of methylene chloride at -30° C. The temperature is allowed to rise slowly to 5° C., whilst stirring, and 3.7 g of 3-(N,N-diethylamino)-2-hydroxypropylamine are added. The reaction solution is subsequently stirred at room temperature, poured into water and worked up as described in Example 8. Yield: 4.5 g of the hydrochloride of the title compound, melting point: 148°-150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH3:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:19])[CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(O)C1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCCC1CCN(c2ccc(Br)cn2)CC1
Temperature: 160 °C

Procedure:
11.00 g (46.43 mmol) of 2,5-dibromopyridine, 6.00 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 mL of DMSO are placed in an autoclave. The mixture is then heated at 160° C. for 20 hours. The reaction mixture is allowed to cool to room temperature and then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[CH:16]([C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)=[O:17].Cl>O>[OH:17][CH2:16][C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cn1ncc(C#Cc2ccc(S(N)(=O)=O)cc2)c1C=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(C#Cc2ccc(S(N)(=O)=O)cc2)c1CO
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Under a nitrogen atmosphere, 1.0 M diisobutylaluminum hydride (1.70 mL, toluene solution) was added dropwise to a tetrahydrofuran (5.0 mL) solution of 4-[(5-formyl-1-methyl-1H-pyrazol-4-yl)ethynyl]benzenesulfonamide (160 mg) at −78° C., and the obtained solution was then stirred for 1 hour. Thereafter, water was added to the reaction solution, and the obtained solution was converted to an acidic solution by addition of 2 M hydrochloric acid. Then, the solution was extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=99:1 to 95:5), so as to obtain the title compound (60 mg) in the form of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[N:29]([CH3:24])[CH2:28][CH2:27][CH3:26])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(Br)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (1.0 g, 3.86 mmol) and HATU (1.76 g, 4.63 mmol) in DMF (35 mL) was stirred at room temperature for 10 min. Then N-methylpropan-1-amine (0.28 g, 0.4 mL, 3.86 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (1.2 g, 99% yield): HPLC retention time: 1.89 min (method A). MS (ESI) (M+H)+ 314.03.
Reaction SMILES: [NH2:1][C@:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([Br:20])[N:14]=1)([CH:10]([F:12])[F:11])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[Br:20][C:15]1[N:14]=[C:13]([C@@:2]2([CH:10]([F:12])[F:11])[CH2:3][C@@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:1]2)[C:18]([F:19])=[CH:17][CH:16]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@](C[C@H](O)C(F)(F)F)(c1nc(Br)ccc1F)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1=N[C@](c2nc(Br)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a 50-mL round-bottomed flask was added (2S,4R)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5,5-pentafluoropentan-2-ol (22 mg, 0.060 mmol) and benzoyl isothiocyanate (8.87 μl, 0.066 mmol) in THF (599 μl). The reaction mixture was stirred at RT for 16 h. To the reaction mixture was added triethylamine (10.00 μl, 0.072 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.64 mg, 0.066 mmol). The mixture was heated at 75° C. for 1.5 h. The reaction mixture was allowed to cool to RT and was diluted with water and extracted with EtOAc. The organic extract was washed with satd NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (22 mg, 0.044 mmol, 74.0% yield) as off-white solid. MS m/z=496, 498 M+, Calculated for C18H12BrF6N3O2: 496.20.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.[NH2:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:38][C@@H:39]4[CH2:44][CH2:43][CH2:42][C@H:41]([OH:45])[CH2:40]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(N[C@@H]2CCC[C@H](O)C2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide and 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and (1S,3R)-3-aminocyclohexanol (152 mg, 1.32 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (230.2 mg, 0.73 mmol, yield 66%). 1H NMR (400 MHz, CD3OD) δ ppm 8.29 (s, 1H), 3.91-3.89 (m, 1H), 3.69-3.62 (m, 1H), 2.50 (s, 1H), 2.29-2.25 (m, 1H), 2.20 (s, 6H), 1.97-1.83 (m, 3H), 1.41-1.21 (m, 4H); MS (ESI) m/z=318.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.[N:12]1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][CH:41]=1)[C:22]([NH:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=C[C:26]=1[N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:23]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][CH:41]=1)[C:22]([NH:24][C:25]1[C:26]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([C:9](=[O:11])[CH2:8][N:4]3[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]3)[CH2:34][CH2:33]2)=[N:12][CH:28]=[C:29]([Cl:31])[CH:30]=1)=[O:23]
Reactant: c1ccncc1
Reactant: O=C(Nc1cc(Cl)ccc1N1CCCNCC1)c1cccc(Cl)c1
Reactant: Cc1cc(C)n(CC(=O)O)n1
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCCN(c3ncc(Cl)cc3NC(=O)c3cccc(Cl)c3)CC2)n1
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To solution of (3,5-dimethyl-pyrazol-1-yl)-acetic acid (0.010 g, 0.068 mmol) in N,N-dimethylformamide (2 mL) is added 0.006 mL (0.071 mmol) of pyridine followed by) tetramethyluroniumhydroxybenzotriazolehexaflourophosphate (0.123 g, 0.324 mmol). The mixture stirred for 1 hour. To this is added 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-phenyl)-benzamide (0.025 g, 0.068 mmol). The mixture is allowed to stir overnight. The mixture is concentrated under reduced pressure and is purified by reverse phase HPLC to provide 0.010 g of 3-chloro-N-(5-chloro-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-[1,4]diazepan-1-yl}-pyridin-3-yl)-benzamide in 29% yield. MS MH+=501.8
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34].O>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:33][CH3:34])=[O:23])=[CH:20][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCI
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C(=O)O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(COc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 40.9 %

Procedure:
2 g (6 mmol) of 4-carboxybenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether, 2.7 g (19.6 mmol) of anhydrous potassium carbonate and 19 g (12.4 mmol) of iodoethane in 18 ml of butanone were refluxed for 7 h. The mixture was then poured into water and extracted with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Recrystallization from methanol resulted in 0.9 g of the title compound of melting point 76°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:28])([CH3:27])[CH2:20][NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:29]C.[CH:31](S(Cl)(=O)=O)=[CH2:32].ClC1C=CC([C:44]2[N:45]=[C:46](C(C)(C)CN)[NH:47][C:48]=2C2C=CN=CC=2)=CC=1OC.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:28])([CH3:27])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][N:47]3[CH2:32][CH2:31][N:45]([CH3:46])[CH2:44][CH2:48]3)(=[O:24])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[OH:29]
Reactant: C=CS(=O)(=O)NCC(C)(C)c1nc(-c2ccc(Cl)c(OC)c2)c(-c2ccncc2)[nH]1
Reactant: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Reactant: C=CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(CCS(=O)(=O)NCC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Temperature: 25 °C
Yield: 38 %

Procedure:
Ethensulfonic acid {2-[4-(4-chloro-3-methoxy-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide A solution of ethenesulfonyl chloride (J. Marchand-Brynaert et al., Tetrahedron 1966, 52, 5591) (230 mg, 1.8 mmol) in dichloromethane (10 ml) was cooled to −78° C. and treated with a solution of the product of Example 2 and triethylamine (0.4 ml, 3 mmol) in dichloromethane (10 ml). After 1 hour the reaction mixture was warmed to room temperature and the solution washed with saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated to give the title compound (254 mg, 38%); MS(ES+) m/e 447/449 [M+H]+. Step 2. 2-(4-Methyl-piperazin-1-yl)-ethanesulfonic acid {2-[4-(4-chloro-3-methoxy-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide A solution of the produce of Step 1 (110 mg, 0.25 mmol) and N-methylpiperazine (50 mg, 0.5 mmol) in dichloromethane (5 ml) was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound (98 mg, 72%); MS(ES+) m/e 547/549 [M+H]+. Step 3. 2-(4-Methyl-piperazin-1-yl)-ethanesulfonic acid {2-[4-(4-chloro-3-hydroxy-phenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-propyl}-amide The title compound was prepared from the product of Step 2 using the method described in Example 3 and the product purified by silica gel chromatography; MS(ES+) m/e 533/535 [M+H]+.