Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C

Procedure:
The title compound was prepared from [2-amino-5-(ethyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J25) (279 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (400 mg, 66%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:17])[C:11]=1[OH:18])(=[O:9])[CH3:8].[CH3:19][O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35]I)=[CH:31][CH:30]=2)[CH:23]=1.C(OCC)(=O)C>CC(C)=O.ClCCl>[CH3:19][O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:7](=[O:9])[CH3:8])=[C:11]([OH:18])[C:12]=3[I:17])=[CH:33][CH:34]=2)[CH:23]=1
Reactant: COC(=O)c1cccc(Cc2ccc(CI)cc2)c1
Reactant: CC(=O)c1ccc(O)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3I)cc2)c1
Temperature: 50 °C
Yield: 61 %

Procedure:
Potassium carbonate (675 mg, 4.88 mmol) is added to a solution of 4-acetyl-3-hydroxy-2-iodo-phenol (925 mg, 3.33 mmol) and 3-(4-iodomethyl-benzyl)-benzoic acid methyl ester (1.21 g, 3.30 mmol) in acetone (65 mL). The resulting suspension is heated at 50° C. for 16 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is taken up in dichloromethane, washed with 1N hydrochloric acid, brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid. This solid is dissolved in dichloromethane and a white precipitate forms upon addition of ethyl acetate. The white solid is filtered off and the mother liquor is purified by flash chromatography, eluting with 20% ethyl acetate in hexanes. The precipitate and chromatographed materials are combined to give 1.04 g of the title compound as a pale yellow solid: MS (m/z) 517 (M+1), 515 (M−1); 1H NMR δ (CDCl3); 13.58 (s, 1H), 7.93 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 7.45-7.38 (m, 4H), 7.25 (d, J=8.0 Hz, 2H), 6.50 (d, J=9.0 Hz, 1H), 5.27 (s, 2H), 4.07 (s, 2H), 3.94 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(O)(=O)C.S([O-])([O-])(=O)=O.[Ca+2]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:13]([CH2:12][O:11][CH3:10])=[CH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COc1ccccc1N
Reactant: COCC(=O)CC(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: COCC(=CC(=O)OC)Nc1ccccc1OC
Yield: 73.5 %

Procedure:
A mixture of 100 g of o-anisidine, 190 g of methyl γ-methoxyacetoacetate, 2.3 ml of acetic acid, 203 g of calcium sulfate and 800 ml of absolute ethanol was refluxed for 16 hours. The residue after filtration and concentration of the filtrate under reduced pressure was taken up in ethyl acetate, the solution was extracted several times with 2 N NaOH and 5% strength citric acid solution and dried over Na2SO4, and the solvent was removed in a rotary evaporator. 150 g of crude product were obtained and were employed without further purification in the following stage.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:22])([F:24])[F:23])[CH:12]=2)[C:8]([NH:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccncn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccncn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 336.6 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (8.32 g, 20.0 mmol) in methylene chloride (100 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (11.14 mL, 22.28 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at 0° C. for 45 min and at 25° C. for 1 h. The reaction mixture was then cooled to 0° C. and treated with a solution of 4-aminopyrimidine (4.02 g, 4.28 mmol) in tetrahydrofuran (60 mL) followed by pyridine (6.0 mL, 74.2 mmol). This solution was stirred at 0° C. for 15 min and at 25° C. for 16 h. At this time, the reaction was poured onto a slurry of ice water (100 g) and then extracted with ethyl acetate (3×250 mL) and ether (1×200 mL). The combined organic layers were washed with water (1×500 mL) and a saturated aqueous sodium chloride solution (3×300 mL). The organic layer was then dried over sodium sulfate and magnesium sulfate, treated with charcoal, filtered through a pad of celite, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide (6.36 g, 72.1%) as a white solid: mp 85–90° C.; [α]23589=−32.53° (c=0.166, chloroform); EI-HRMS m/e calcd for C20H22F3N3O3S (M+) 441.1334, found 441.1333.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH:31]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:38]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:39])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)NC1CCCCC1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 26.8 mg (0.21 mmol) of cyclohexyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 23.4 mg (47.3% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:31]=[N:30][C:29]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:36][CH2:37][N:32]([C:29]4[N:30]=[N:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:33][CH2:34]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(c2ccc(Cl)nn2)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(Cl)nn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(6-chloro-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-chloro-3-pyridazinyl)-4-piperidinecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 572.2 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:7][CH2:6][CH2:5]2.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc2c(cc1N)CCC2
Yield: 97.6 %

Procedure:
A solution of 200 mg (1.12 mmol) of 5-amino 6-nitroindan and 1.14 g (6.01 mmol) of SnCl2 in 8 mL of ethanol was heated at 70° C. for 2 h. It was evaporated to remove the ethanol. The residue was treated with 40% aqueous NaOH to pH =12. The mixture was diluted with 4 mL of water and extracted with CHCl3(3×10 mL). The extract was dried (MgSO4) and evaporated to leave a yellow crystalline solid (162 mg, 97%). 1H NMR (CDCl3), 2.012 (m, 2), 2.173 (t, 4, J=7.25), 3.301 (sb, 4), 6.614 (s, 2).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH3:34].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH3:32][N:33]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)C)c4)cc23)CC1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for 5 h before addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was then stirred overnight. Compound was purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (19.2%).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=1)C(OC)=O)#[N:2].[Cl-].[Na+].O.CS(C)=O>C(OCC)(=O)C>[CH3:15][S:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([CH2:3][C:1]#[N:2])[CH:13]=1
Reactant: COC(=O)C(C#N)c1cc(SC)ncn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1cc(CC#N)ncn1
Temperature: 160 °C
Yield: 56.3 %

Procedure:
A microwave vial was charged with methyl cyano[6-(methylthio)-4-pyrimidinyl]acetate (Intermediate 14, 700 mg, 3.14 mmol), sodium chloride (1.0 g, 17.11 mmol), water (1 mL) and DMSO (19 mL). The mixture was stirred and heated at 160° C. for 50 minutes in the microwave. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Fractions containing the suspected product were combined and concentrated under reduced pressure to give the title compound (292 mg) as a yellow oil;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][O:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:57]([O:56][CH2:55][CH2:54][CH2:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH3:58]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(3-ethoxypropoxy)phenyl borate (207 mg) and potassium carbonate (234 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was refluxed for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(3-ethoxypropoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 99) (140 mg).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[Br:10][C:11]1[C:12](Cl)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]>CC#N.CCOCC>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH2:6][C:13]([C:14]#[N:15])([CH3:12])[CH2:9][CH2:7]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Temperature: 80 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
To a solution of 4-methylpiperidine-4-carbonitrile, HCl (1.0 g, 6.22 mmol) and DIEA (4.4 mL, 24.9 mmol) in anhydrous CH3CN (30 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.1 g, 6.22 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 72 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 1.0 g (38%). 1H NMR (500 MHz, DMSO-d6) δ 5.08-5.03 (m, 1H), 3.54-3.40 (m, 4H), 2.61 (s, 3H), 2.30 (s, 3H), 1.92 (d, J=12.4 Hz, 2H), (2H missing), 1.35 (s, 3H), 1.28 (d, J=5.9 Hz, 6H). UPLC (M+H)=424.3.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([CH2:10][OH:11])[C:5]1=[O:12])[C:2]#[CH:3].[CH3:13][C:14]1([CH3:25])[C@H:16]([CH:17]=[C:18]2[CH2:21][CH2:20][CH2:19]2)[C@H:15]1[C:22](O)=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][C:14]1([CH3:25])[C@H:16]([CH:17]=[C:18]2[CH2:19][CH2:20][CH2:21]2)[C@H:15]1[C:22]([O:11][CH2:10][N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH2:1][C:2]#[CH:3])[C:5]1=[O:12])=[O:23]
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)O
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](C=C3CCC3)C2(C)C)C1=O
Yield: 17 %

Procedure:
A solution of 3.6 g of (1-propargyl-2,4-dioxo-imidazolidin-3-yl)-methanol in 10 ml of methylene chloride was added at 20° C. to a mixture of 4 g of (1R,trans)2,2-dimethyl-3-(cyclobutylidenemethyl)-cyclopropane-1-carboxylic acid, 4.6 g of dicyclohexylcarbodiimide, 20 ml of methylene chloride and a catalytic amount of 4-dimethylamino-pyridine and the mixture was stirred at 20° C. for 17 hours and was vacuum filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl actate mixture and then a 95-5 benzene-ethyl acetate mixture yielded 1.2 g of (1-propargyl-2,4-dioxo-imidazolidin-3-yl)-methyl(1R,trans)2,2-dimethyl-3-(cyclobutylidenemethyl)-cyclopropane-1-carboxylate.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:23]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[N:22]=1.BrC1C=C(C2C(=O)N(C)C(Cl)=NC=2C2C=CN=CC=2)C=CC=1>ClCCl>[CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:23]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[N:22]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1
Reactant: CC(C)NC[C@H]1CCCN1
Agent: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2c(-c3ccncc3)nc(N3CCCC3CNC(C)C)n(C)c2=O)c1
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.13 g, 0.6 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.28 mL diisopropylethylamine (1.6 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-3-methyl-6-pyridin-4-yl-5-m-tolyl-3H-pyrimidin-4-one (0.16 g, 0.5 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. (This meta-methyl chloro-intermediate was synthesized by a similar procedure as that of 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.) The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.219 g as pale yellow solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][P:6](Cl)(=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[CH2:14]([Si:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH3:22])[CH2:19][CH2:20][OH:21])[CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[P:6]([O:21][CH2:20][CH2:19][Si:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:12]
Reactant: CCCC[Si](C)(CCO)CCCC
Reactant: CCCCOP(=O)(Cl)OCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCOP(=O)(OCCCC)OCC[Si](C)(CCCC)CCCC
Reaction time: 8 h

Procedure:
Dibutylphosphorochloridate (3.74 g) was added to a solution of 2-(di-n-butyl methylsilyl)-ethanol (3 g) and pyridine (1.04 g) in carbon tetrachloride (10 ml). The mixture was left overnight, filtered, and the filtrate passed through an alumina column (20 g), eluting with a further 3 × 20 ml of carbon tetrachloride. Removal of the solvent under vacuum left the phosphate as a colourless oil (2.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7](=S)[NH:6][C:5]2=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1.O=P(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:18][C:7]1[O:8][C:4]2[C:5](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(Cl)cc2oc(=S)[nH]c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)cc2oc(Cl)nc12
Temperature: 125 °C
Yield: 99.1 %

Procedure:
A mixture of the product from Step A (2.00 g, 8.20 mmol), POCl3 (1.26 g, 8.21 mmol), and PCl5 (1.71 g, 8.21 mmol) was heated to 125° C. for 2.5 hours. The reaction mixture was dried under high vacuum for 24 hours to afford methyl 2,6-dichlorobenzoxazole-4-carboxylate (2.00 g, 99%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 4.04 (s, 3H); MS (ESI+) m/z 247 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:8]([C:9]#[N:10])[CH2:7][CH:6]2[CH2:11][CH:4]1[C:5]2([CH3:13])[CH3:12])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([CH:3]1[CH:8]([CH2:9][NH2:10])[CH2:7][CH:6]2[CH2:11][CH:4]1[C:5]2([CH3:12])[CH3:13])[CH3:2]
Reactant: CCC1C(C#N)CC2CC1C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(CN)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
2-Ethyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile (288 mg, 1.65 mmol) was dissolved in anhydrous THF (10 ml) under an atmosphere of dry N2. To the reaction was added a 1.0 M solution of lithium aluminum hydride (4.0 ml) in THF. The reaction was stirred at ambient temperature for 16 hr and was then quenched by the sequential slow addition of 152 μl of water, 152 μl of 15% NaOH and finally 460 μl of water. The reaction was stirred for an additional 2 hr after which time it was filtered and the filter cake was washed with CH 2Cl2. The combined filtrate was concentrated under vacuum to give 267 mg of the titled compound: 1H NMR (CD3OD) 6 2.73 (dd, J=4.6,12.2 Hz, 1H), 2.41 (dd, J=9.5, 12.2 Hz, 1H), 2.32 (m, 1H), 2.19 (m, 1H), 1.98 (m, 1H), 1.91 (m, 1H), 1.74 (m, 1H), 1.28-1.57 (m, 4H), 1.20 (s, 3H), 0.99 (s, 3H), 0.89 (t, J=7.2 Hz, 3H), 0.74 (d, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[CH:6][CH:7]=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[Br:16]Br>C(O)(=O)C.O>[Br:16][C:7]1[CH:6]=[C:5]([CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(C)c(OCC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(C)cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5-ethoxy-4-methylbenzoate (500 mg, 2.40 mmol) in acetic acid (10 mL) and water (10 mL) at room temperature was added bromine (385 mg, 2.40 mmol). The resulting reaction mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with hexanes/ether (80/20). Layers were separated and the organic layer was washed with saturated Na2CO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to yield the title intermediate (660 mg, 2.23 mmol) as light yellow solid.