Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 53.5 %

Procedure:
3-Bromo-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine (0.10 g, 0.36 mmol) and 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (0.15 g, 0.47 mmol) were coupled following the procedure in Example 1 to afford 4-fluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white amorphous solid (75 mg, 53%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.09 (1H, s), 7.19 (1H, dd, J 7 and 7), 7.30 (1H, ddd,J 8, 8 and 3), 7.49-7.58 (3H, m), 7.64-7.66 (2H, m), 7.73-7.75 (2H, m), 8.33 (1H, d, J 7); m/z (ES+) 390 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25]([OH:27])=O)[C:4]=12.[Cl-].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([N:41]2[CH2:46][CH2:45][NH2+:44][CH2:43][CH2:42]2)=[N:39][N:38]=[N:37]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25](=[O:27])[N:44]3[CH2:43][CH2:42][N:41]([C:40]4[N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)[N:37]=[N:38][N:39]=4)[CH2:46][CH2:45]3)[C:4]=12
Reactant: c1ccc(-n2nnnc2N2CC[NH2+]CC2)nc1
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (15 mg, 0.039 mmol), 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-ium chloride (11.43 mg, 0.043 mmol), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (13.71 mg, 0.043 mmol) and N,N-diisopropyl ethylamine (0.022 ml, 0.124 mmol) in DMF (1 ml) was stirred overnight at room temperature. The reaction mixture was filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give N-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (10 mg, 43%) as white solid. LCMS: m/e 600.47 (M+H)+, ret time 2.67 min (method 4). 1H NMR (500 MHz, DMSO-D6) δ ppm 1.22 (s, 9H) 3.23-3.29 (m, 2H) 3.39-3.49 (m, 4H) 3.68-3.74 (m, 2H) 3.99 (s, 3H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.88 (s, 1H) 8.13-8.18 (m, 1H) 8.21 (s, 1H) 8.23 (d, J=3.66 Hz, 1H) 8.64-8.69 (m, 1H) 11.36 (s, 1H) 12.59 (d, J=3.36 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[N:5]=[C:4]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]=1[C:23]1[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=1[F:31]>CO.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]([C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])=[C:2]([Cl:1])[N:7]=2)=[N:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(-c3c(F)cc(F)cc3F)c(NCC(F)(F)F)n2)nc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(Cl)c(-c3c(F)cc(F)cc3F)c(NCC(F)(F)F)n2)nc1
Temperature: 100 °C
Yield: 104.8 %

Procedure:
A mixture of 6-chloro-2-(5-nitropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (101 mg, 0.22 mmol) and Iron powder (256 mg, 4.58 mmol) in 2 mL of methyl alcohol and 1 mL of acetic acid is heated at 100° C. for 1 h. The reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and then with saturated sodium chloride, dried over magnesium sulfate, filtered, concentrated and dried under reduced pressure to yield 2-(5-aminopyridin-2-yl)-6-chloro-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light yellow oil (100 mg). MS: m/z 434.2 (M+H). This product is used in the next step with out further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](O)[CH:17]=[CH2:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl>[CH2:18]([O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:17]=[CH2:16]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 40.9 %

Procedure:
To a solution of N-(tert-butyloxycarbonyl)-L-valine (10.53 g; 48.5 mmol) and allyl alcohol (33 mL; 49 mmol) in 150 mL CHCl3 at 0° C. was added HOBt (8.53 g; 63.1 mmol) then EDCI (13.88 g, 72.4 mmol). The final mixture was stirred at 4° C. for 12 h then poured in to 100 mL NH4OAc (25%). The organic phase was separated. The aqueous phase was washed with 50 mL of CHCl3. The organic phases were combined, dried over Na2SO4, concentrated and flash chromatographed on silica gel (hexane/EtOAc 9:1) to yield 5.10 g (41 %) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([OH:28])([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:6][CH2:7][CH3:8])C.[OH-].[Li+]>O1CCCC1.O>[OH:28][C:5]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:4]([OH:29])=[O:3]
Reactant: CCCC(O)(C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 61.1 %

Procedure:
A mixture of 600 mg (2 mmol) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid ethyl ester in 8 ml tetrahydrofuran and of 70.0 mg (2 mmol) lithiumhydroxide in 4 ml water was stirred overnight at room temperature. The solvent was evaporated and the residue extracted at pH 1 with ethylacetate to yield 450 mg (81%) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid, MS (m/e): 367.1 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=1.[OH-].[Na+]>O1CCCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:23])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 94 %

Procedure:
The ester of (A) above (19.5 g, 63.4 mmol) is dissolved in tetrahydrofuran (150 ml) and 1N NaOH (150 ml) is added. The reaction is heated at reflux for 3 hours. The tetrahydrofuran is removed in vacuo and the remaining solution is adjusted to pH 3 using 1N HCl. A precipitate forms which is filtered and dried, giving 17.5 g (94% yield) of product, m.p. 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]#[N:19].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Reaction time: 4 h

Procedure:
To a partially dissolved solution of piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 10 mmol) in THF (30 mL) is added 60% NaH (0.44 g, 11 mmol). The resulting solution is stirred for 5 min before the addition of bromoacetonitrile (0.9 mL, 13 mmol). The reaction is stirred for 4 h. MeOH (1 mL) is added and the solution is concentrated and the residue is diluted with EtOAc, washed with 1 N HCl, H2O, NaHCO3 and the solution is dried over MgSO4. The filtrate is concentrated and the crude product is chromatographed using a silica column (50% EtOAc/PE-EtOAc) to yield 4-cyanomethyl-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, CDCl3) δ4.41 (s, 2H), 4.16 (s, 2H), 3.75 (t, 2H), 3.51 (t, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[CH:36]1([C:42]([O:44][CH:45](I)[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CCOCC.[ClH:55]>CC(N(C)C)=O>[ClH:55].[ClH:55].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:45]([O:44][C:42]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[O:43])[CH:46]([CH3:48])[CH3:47])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(C)C(I)OC(=O)C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CC(C)C(OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12)OC(=O)C1CCCCC1
Temperature: 0 °C

Procedure:
In 120 ml of dimethylacetamide is dissolved 6.0 g of potassium 7β[2-(2-aminothiazol-4-yl) acetamido]-3-[[[1-(2-dimethylaminoethyl) -1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylate and the solution is cooled to 0° C. With stirring, 9.0 g of 1-iodo-2-methylpropyl cyclohexanecarboxylate is added at one stroke to the solution, followed by stirring for further 10 minutes. To the reaction mixture is added 70 ml of 2 N HCl-ether, followed by addition of 300 ml of ether. The ether layer is discarded and the residue is dissolved in 50 ml of 1 N hydrochloric acid and subjected to column chromatography on XAD-II ®resin (Rohm & Haas Co. U.S.A.), elution being carried out with water-acetonitrile (3:1). The fractions containing the desired product are combined, evaporated under reduced pressure to remove the solvent and lyophilized to give 2.5 g of the title compound as a colorless powder.
Reaction SMILES: C([O:4][C:5]([C:7]1([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])CC.CC([O-])(C)C.[K+].O.OS(O)(=O)=O>C1COCC1>[CH2:17]([CH:14]([CH2:15][CH3:16])[CH2:13][C:7]1([C:5]([OH:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:18]
Reactant: CCCOC(=O)C1(CC(CC)CC)CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 54 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid n-propyl ester (2.3 g, 9.04 mmol) was added dropwise under stirring to a solution of KOtBu (4.058 g, 36.2 mmol) in THF (17 mL) containing a small amount of water (244 mg, 13.6 mmol). The mixture was stirred 20 h at 54° C., cooled to room temperature, slowly poured onto a mixture of ice and 4N H2SO4 and extracted with DCM (2×150 mL) after adjusting to pH 1. The organic phases were washed with diluted aq. NaCl (100 mL), combined, dried over sodium sulfate and concentrated to afford 1.901 g (99%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 96% (GC area).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH:40]1[CH2:42][CH2:41]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: BrCC1CC1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CC3CC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and (bromomethyl)cyclopropane (0.174 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.80 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.58 g) was obtained.
Reaction SMILES: C(O)CCO.I.[C]=O.[CH:9]([OH:13])([OH:12])[CH2:10][CH3:11].OCCCI.[C:19]1(=[O:24])[O:23]CC[CH2:20]1>O>[C:19]([OH:24])(=[O:23])[CH2:20][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: CCC(O)O
Reactant: O=C1CCCO1
Agent: I
Agent: OCCCI
Agent: [C]=O
Solvent: O
Solvent: OCCCO
Product: O=C(O)CCCC(=O)O
Temperature: 175 °C
Reaction time: 6 h

Procedure:
A solution containing 2 mls 1,3-propanediol, 15 mls water, 3 mls of 57% hydriodic acid and 0.1 g RhCl3.XH2O were placed in an autoclave, pressurized with 1200 psi of carbon monoxide, and heated with shaking at 175° C. for 6 hours. Analysis indicated the presence of 7.8 millimoles of gamma-butyrolactones (28.2% conversion based on the propanediol introduced). Unreacted propanediol and 3-hydroxypropyliodide were also present. The solution was returned to the autoclave, pressurized with 1100 psi of carbon monoxide and heated with shaking at 175° C. for 6 hours more. The product now contained 15.1 millimoles of gamma-butyrolactone (54.4% conversion), but some 3-hydroxypropyliodide was also present. No glutaric acid was formed.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:13]=[CH:12][N:11]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccnc(Cl)n1
Yield: 70 %

Procedure:
2,2,2-Trifluoroethanol (51.3 ml) in DMF (135 ml) was added to a suspension of sodium hydride (29.5 g) in DMF (335 ml) keeping the temperature below 10° C. After 1 hour the resulting mixture was added to a solution of 2,4-dichloropyrimidine (100 g) in DMF (330 ml) keeping the temperature between -5° and -10° C. 1 Hour later the resulting reaction mixture was poured into water (1 l) and extracted with ethyl acetate (3×400 ml). The combined extracts were washed with brine, dried and concentrated to give 70% pure 2-chloro-4-(2,2,2-trifluoroethoxy)-pyrimidine (142 g) as a pale orange oil; 1H NMR (270 MHz): δ4.78(2H,q), 6.83(1H,d), 8.42(1H,d) ppm.
Reaction SMILES: [CH2:1]([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][NH2:3].[F:10][C:11]([F:18])([F:17])[C:12]([O:14]CC)=O>O1CCCC1>[F:18][C:11]([F:10])([F:17])[C:12]([NH:3][CH2:2][CH2:1][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:12](=[O:14])[C:11]([F:18])([F:17])[F:10])=[O:14]
Reactant: NCCCNCCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCCNCCCNC(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C

Procedure:
35 g of 3,3′-iminobispropylamine (266.7 mmol) were solubilized in 150 ml of anhydrous tetrahydrofuran under an argon stream. The reaction mixture was then cooled to 0° C. on an ice bath and 65 ml of ethyl trifluoroacetate (546.8 mmol) were added dropwise (very slowly) using a dropping funnel. At the end of the addition (3 hours later), the reaction mixture was allowed to return to room temperature and the stirring was maintained for a few hours under argon.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:15]=3[CH3:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: Cc1ccc(C)c(CN)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2,5-dimethyl-benzylamine (87 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2,5-dimethyl-benzylamino)-2H-phthalazin-1-one: 31 mg (17.0%): m/z (M+H)=314. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.92 (d, 1H), 7.45 (m, 1H), 7.16 (dd, 1H), 7.10 (m, 2H), 6.99 (m, 1H), 6.85 (s, 1H), 4.32 (d, 2H), 2.29 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]([CH3:35])[CH3:34])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH:25]=2)[CH:19]=1)=[O:13]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]([CH3:35])[CH3:34])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC(C)(C)NC(C)(C)C3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.07 g, 0.147 mmol) in MeOH (2 mL) was added 10% Pd/C in catalytic amount and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3 hr. On completion of reaction, filter it through celite bed, then filtrate was concentrated under reduce pressure. The crude material was purified by column chromatography to give the desired compound (71% yield). LCMS: 479.20 (M+1)+; HPLC: 99.04% (@ 254 nm), (Rt; 5.075); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.70 (t, 1H), 8.27 (s, 1H), 7.70 (bs, 1H), 7.53 (s, 1H), 5.89 (s, 1H), 5.22-5.15 (m, 1H), 4.38 (d, 2H, J=5.2 Hz), 3.57 (m, 1H), 2.22 (s, 3H), 2.12 (s, 3H), 2.00-1.90 (m, 2H), 1.90-1.80 (m, 2H), 1.50 (s, 6H), 1.49 (s, 9H), 1.40 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[C:11](=[O:19])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[Br:18][C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[NH:8][CH2:9][CH2:10][C:11]2=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(Br)cnc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1CCNc2ncc(Br)cc21
Reaction time: 16 h
Yield: 88.5 %

Procedure:
6-Bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (628 mg, 1.92 mmol) is dissolved into 3 mL of MeOH and 3 mL of 4 M HCl/1,4-dioxane is added. The mixture is stirred for 16 h and concentrated to dryness. The residue is dissolved into 10 mL CH2Cl2 and 10 mL of H2O and neutralized with saturated aqueous Na2CO3 solution. The aqueous layer is extracted with 2×20 mL of CH2Cl2. The organic phase is dried with MgSO4, filtered and concentrated to give 386 mg of 6-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[SH:12]>C(O)(=O)C>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([SH:12])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S
Solvent: CC(=O)O
Product: COc1cc(N)ccc1S
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.8 %

Procedure:
To 2-methoxy-4-nitrobenzenethiol (7.0 g) was added acetic acid (70 ml), reduced iron (21 g) was added to the mixture, and the mixture was stirred for 6 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-amino-2-methoxybenzenethiol (3.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:19]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17]O)=[CH:16][N:11]2[N:10]=1.P(Br)(Br)[Br:21]>C(Cl)Cl>[Br:21][CH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])[N:19]=2)[CH:16]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(CO)cn2n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc2ccc(CBr)cn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of (2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (148 g, 0.584 mol) in DCM (2.96 L) is added PBr3 (237.3 g, 0.877 mol) at −40° C. The reaction mixture is allowed to warm to temperature and then stirred for a further for 2 hours at room temperature. The reaction is cooled to 0° C., quenched with ice cold water (1.5 L) and saturated sodium bicarbonate solution is added to adjust the pH ˜7.5 to 8. The mixture is diluted with DCM (2 L), the aqueous layer is separated and extracted with DCM (3 L). The organic extracts are combined, washed with water (2×3 L) and brine solution (3 L), dried the organic extracts over sodium sulphate, filtered and evaporated to dryness to give the title compound (140 g, 76%). LCMS m/z 316/318 79Br/81Br (M+H)+.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH2:56][CH3:57])[C:50]=3[C:49](=[O:58])[N:48]2[C:59]2[CH:60]=[C:61]([CH3:69])[C:62]3[N:63]([C:65]([CH3:68])=[N:66][N:67]=3)[CH:64]=2)=[C:43]([F:70])[CH:42]=1>CC(O)C>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH2:56][CH3:57])[C:50]=3[C:49](=[O:58])[N:48]2[C:59]2[CH:60]=[C:61]([CH3:69])[C:62]3[N:63]([C:65]([CH3:68])=[N:66][N:67]=3)[CH:64]=2)=[C:43]([F:70])[CH:42]=1
Reactant: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)C2c1ccc(Cl)cc1F
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CC(C)O
Product: CCn1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3c1)[C@@H]2c1ccc(Cl)cc1F

Procedure:
The title compound (52 mg, 47% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: MGII preparative SFC; column: Chiralpak AD-H, 30×250 mm; mobile phase: scCO2/iPrOH 60:40; flow: 50 mL/min; temperature: 38° C.; detection UV: 220 nm) of the racemic mixture of 4-(4-chloro-2-fluorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-ethyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 185).