Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](=[CH:8]/[CH:9]([CH3:15])[CH2:10][P:11]([OH:14])([OH:13])=[O:12])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:16][C:17]1[CH:24]=[CH:23]C(CO)=[CH:19][CH:18]=1.Cl>ClCCl>[NH2:1]/[C:2](=[CH:8]/[CH:9]([CH3:15])[CH2:10][P:11]([OH:14])([OH:13])=[O:12])/[C:3]([O:5][CH2:6][C:7]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:4]
Reactant: CCOC(=O)/C(N)=C\C(C)CP(=O)(O)O
Reactant: OCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(/C=C(/N)C(=O)OCc1ccc(Cl)cc1)CP(=O)(O)O

Procedure:
A mixture of 2.37 g (10 mmols) of ethyl E-2-amino-4-methyl-5-phosphono-pentenoate, 14.3 g (100 mmols) of p-chlorobenzyl alcohol, 10 ml of dichloromethane and 20 ml of 4 N hydrochloric acid is allowed to stand at room temperature for 1 week. The reaction mixture is evaporated to dryness, the residue is dissolved in 25 ml of ethanol and a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise. The crystalline precipitate formed is collected, washed twice with water, filtrated and dried. p-chlorobenzyl E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 207°-208° is thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].ClCCl.Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(-c3cc(OCCN(CC)CC)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 140 °C

Procedure:
Cesium carbonate was added to a solution of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in DMF, 2-Bromo-N,N-diethylethylamine hydrobromide was added and the suspension heated, at ˜140° C., for ˜2 hrs. The resulting suspension was allowed to cool and dichloromethane added. The mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a dark brown gum. The crude product was purified by chromatography on silica eluting with mixtures of dichloromethane and methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([O:16][CH3:20])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a solution of Example 203A (363 mg, 1.56 mmol) in THF (7 mL) at 0° C. was added NaH (373 mg, 9.34 mmol) and stirring was continued for 15 min. Iodomethane (0.78 mL, 12.45 mmol) was added and the solution was allowed to warm to room temperature and stirred for 18 h. Solution was quenched with H2O, diluted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and solvent removed to give the title compound (165 mg, 0.67 mmol, 43%). MS (ESI) m/z 248 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[O:7])=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2c(F)cccc2F)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1c(F)cccc1F
Yield: 55 %

Procedure:
A mixture of 233 mg (1 mmol) of 4-methyl-2′,6′-difluorobenzophenone, 178 mg (1 mmol) of recrystallized N-bromosuccinimide, 17 mg benzoyl peroxide, and 3 mL CCl4 were refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4 until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under vacuum. The crude product was purified by column chromatography on a silica gel flash column (13 cm×55 mm) eluted with ethyl acetate/hexane (15:85) and then concentrated under vacuum. The product was allowed to dry under high vacuum overnight. The resultant yield was 55%. Rf=0.3 (ethyl Acetate/hexane; 15:85). 1H-NMR: δ 7.84 (d, 2H, aromatic), 7.50 (d, 2H, aromatic), 7.46 (t, 1H, aromatic), 7.01 (m, 2H, aromatic), 4.51 (s, 2H). 13C-NMR (CDCl3): δ 188.1 (carbonyl); 160.8, 158.8, 143.9, 136.6, 132.0, 130.0, 129.4, 111.9 (aromatic), 31.8 (alkyl bromide).
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[BrH:16].OO>>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([Br:16])=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: COCCOC(=O)c1cccc(C)c1N
Reactant: Br
Agent: OO
Product: COCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 88.3 %

Procedure:
The above-described method (Example 1) was repeated to react 2-methoxyethyl 2-amino-3-methylbenzoate (7.00 g, 33.4 mmol) with hydrogen bromide (5.92 g, 35.1 mmol, 48% in water) and hydrogen peroxide (4.17 g, 36.7 mmol, 30% in water) and, following working up similar to Example 1, 2-methoxyethyl 2-amino-5-bromo-3-methylbenzoate (8.50 g, 80.7% of theory, 91.5 area % LC) was obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH:45]([F:47])[F:46])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]3[N:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:30]=3)[N:9]=2)[CH:7]=1.Cl.C(#N)C.O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH:45]([F:47])[F:46])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]3[N:27]=[N:28][N:29]([CH:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)[CH:30]=3)[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)nn2)CC1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: O
Product: O=C(Nc1cn(Cc2cn(C3CCNCC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.5 %

Procedure:
To a solution of tert-butyl 4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carboxylate (1.98 g, 2.96 mmol) in methanol (30 mL) was added concentrated HCl aqueous solution (15 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 1.85 g crude product, which was sufficient for next step without further purification. A small portion was purified for characterization and biological submission. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (10 mmol NH4HCO3)=18% increasing to ACN/H2O (10 mmol NH4HCO3)=49% within 9 min; Detector, UV 254 nm. 42.1 mg product was obtained. This resulted in 42.0 mg of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 36) [M+H]+=569.2, RT=2.59 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.69 (s, 1H), 9.34 (d, 1H, J=6.4 Hz), 8.68-8.64 (m, 2H), 8.40 (s, 1H), 8.22 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.06 (t, 1H, J=73.4 Hz), 5.49 (s, 2H), 4.58-4.51 (m, 1H), 3.05-3.02 (m, 2H), 2.62-2.57 (m, 1H), 2.30-2.25 (br, 1H), 2.01-1.98 (m, 2H), 1.87-1.73 (m, 2H).
Reaction SMILES: C(O)C.[C:4]([O:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:27]([O:29]CC2C=CC(OC)=CC=2)=[O:28])[C@H:15]([CH3:16])[CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>[Pd].O>[C:4]([O:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:27]([OH:29])=[O:28])[C@H:15]([CH3:16])[CH2:14][NH:13][CH2:12]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
Ethanol (50 ml) and 10% Pd/C (500 mg) were added to 1-benzyl 3-(4-methoxyphenyl)methyl (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 2i (2.92 g, 5.87 mmol), followed by stirring at mom temperature for 38 hours and five minutes under a hydrogen atmosphere. Water (100 ml) was added to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give the title compound (1.37 g, yield: 95.9%).
Reaction SMILES: C([O:4][CH:5]1[CH2:13][CH:8]2[O:9][C:10](=[O:12])[CH2:11][CH:7]2[CH:6]1[CH2:14][O:15]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.C(OCC)C>CO>[OH:4][CH:5]1[CH2:13][CH:8]2[O:9][C:10](=[O:12])[CH2:11][CH:7]2[CH:6]1[CH2:14][OH:15]
Reactant: CC(=O)OCC1C(OC(C)=O)CC2OC(=O)CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: O=C1CC2C(CC(O)C2CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
To a solution of 50 (10.0 g, 39 mmol) in MeOH (100 mL) was added potassium carbonate (15 g). The suspension was stirred at room temperature for 3 hours. To the suspension was added ethyl acetate (60 mL). The resulting suspension was filtered through a pad of diatomaceous earth (Celite®). The filtrate was concentrated in vacuo to give crude product. The crude product was dissolved in MeOH (15 mL) and to it was added diethyl ether (100 mL). The resulting suspension was stirred for 2 hours at room temperature. The solid was filtered to give the title compound (3.62 g, 54%).
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18](O)=[O:19])=[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:31][NH:32][C:18]([C:15]1[N:16]([CH3:17])[C:11]([CH:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[NH2:30])=[CH:12][C:13](=[O:29])[C:14]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (400.0 mg, 0.935 mmol) in dimethylformamide (10 mL) were added HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (426.17 mg, 1.12 mmol) and diisopropylethylamine (1.08 mL, 6.54 mmol). The mixture was stirred for 30 min., thenmethylamine hydrochloride salt (189.31 mg, 2.80 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (15-01) (180.0 mg, 43.62%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([NH2:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(N2CCOCC2)cc1N

Procedure:
A solution of 5-morpholin-4-yl-2-nitro-phenylamine (4.0 g, 0.02 mol) in acetic acid (100 mL) and ethanol (100 mL) was treated with hydrogen gas (60 psi) for 30 min in the presence of palladium on carbon catalyst (0.5 g, 10% Pd). The catalyst was removed by filtration through CELITE®, and the filtrate was concentrated to a syrup and dried in vacuo to afford the intermediate 4-morpholin-4-yl-benzene-1,2-diamine as a crude green solid (3.2 g).
Reaction SMILES: [CH2:1]([N:3]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[C:18]=1[CH3:31])[CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH3:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:17]1[C:18]([CH3:31])=[C:19]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 4-{ethyl[3-(methoxycarbonyl)-2-methyl-5-(trifluoromethyl)phenyl]amino}piperidine-1-carboxylate (4.50 g, 10.1 mmol) in CH2Cl2 (50 mL) was added TFA (5 mL). The reaction mixture was stirred at rt for 18 hours. Then reaction mixture was concentrated in vacuo to give the titled compound as a crude product (7.70 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1C#Cc1c(-c2ccccc2)noc1C
Yield: 82 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol) was converted (using methyl 2-iodobenzoate instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=100:0 to 80:20, 166 mg, 82%) which was obtained as an off-white solid. MS: m/e=318.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(B(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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cn2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1 M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp ° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[C:21](OCC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>C1COCC1>[OH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21](=[O:29])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
To a N2 purged 250 mL RBF is added 30 mL of THF and diisopropylamine (12.0 mL, 86 mmol). The solution is cooled to −78° C. and nBuLi (50 mL, 1.6 M) is added and the solution is warmed to 0° C. for 45 min. The solution is cooled to −78° C. and t-butyl acetate (7.1 mL, 53 mmol) in 12 mL THF is added dropwise over 10 minutes. After 90 min., ethyl salicylate (2.2 mL, 15 mmol) in 15 mL of THF is added. The solution is allowed to warm to RT overnight and quenched with 90 mL of aq. NH4Cl (sat.), extracted with EtOAc (2×25 mL), washed brine (40 mL), dried Na2SO4, filtered, concentrated in vacuo. Purified via column chromatography (silica gel, 10% EtOAc/hex) to give 2.65 g of pale yellow oil (75% yield). IR (film) 2980.2; 2934.9; 1733.6; 1643.7; 1146.6; 757.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.93 (s, 1H); 7.68 (d, J=7.9 Hz, 1H); 7.51 (t, J=7.3, 1H); 7.01 (d, J=8.2 Hz, 1H); 6.93 (t, J=7.3 Hz, 1H); 3.93 (s, 2H); 1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 198.7, 165.8, 162.3, 136.6, 130.3, 118.8, 118.7, 118.3, 82.1, 46.9, 27.6; LRMS (electrospray): Mass calculated for C13H16O4, [M]+, 236.10. Found, [M+23]+259.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH:25]3[CH2:26][O:23][CH2:24]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CCNCC2)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(C2CCN(C3COC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
In a round-bottomed, single-necked, 100-mL flask were placed 4-(4-bromophenyl)piperidine (500.0 mg, 2.08 mmol), N,N-diisopropylethylamine (0.36 mL, 2.08 mmol), 3-oxetanone (0.27 mL, 4.16 mmol), and sodium triacetoxyborohydride (1544.5 mg, 7.3 mmol) in THF (15 mL). The mixture was stirred at room temperature for 16 h. Then, it was quenched with water and the organic layers extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% Hexane to 100% EtOAc) to give 350.0 mg (57%) of 4-(4-bromophenyl)-1-(oxetan-3-yl)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:19][C:9]1([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C2(O)CCC(=O)CC2)cn1

Procedure:
8-(6-Methoxy-pyridin-3-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (4.00 g, 15.7 mmol) as prepared in the previous step was treated with 1N HCl (˜16 mL) in acetone (20 mL) at room temperature for 4 hours. The reaction was neutralized with saturated NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1Nc1nc(Cl)ncc1Cl

Procedure:
The mixture ethyl 3-amino-1H-pyrazole-4-carboxylate (80 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and sodium carbonate (53 mg, 0.5 mmol) in 3 mL of EtOH is heated at 40° C. over night. The precipitate is filtered, washed by cold EtOH, and dried in vacuo to afford ethyl 3-(2,5-dichloropyrimidin-4-ylamino)-1H-pyrazole-4-carboxylate; ESMS m/z 302.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][N:7]([C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCC(C)C1
Yield: 85.5 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-58) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 2.6 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-58). This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(C)(C)C)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(C)(C)C)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(2,2-dimethyl-propylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.