Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[S:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][N:43]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:38][C:39]5[S:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][N:43]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3nnc(C(F)(F)F)s3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (102 mg, 0.601 mmol) and diisopropylethylamine (0.143 mL, 0.819 mmol), and stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with methylene chloride provided the title compound (308 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][N:3]=1.[OH-:23].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]([NH2:16])=[O:23])=[CH:4][N:3]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Temperature: 110 °C

Procedure:
To 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (49 mg, 0.16 mmol, from Example 15) suspended in ethanol (1 mL) was added sodium hydroxide (64 mg, 1.60 mmol, dissolved in 1 mL water). The reaction was heated at 110° C. for 5 hours, cooled, and washed with dichloromethane (25 mL). The dichloromethane layer was concentrated and purified by preparatory TLC plates (92/8/0.5 dichloromethane/methanol/ammonium hydroxide) to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide as white solid (9 mg, 17%, MS (M+H)=318), which was converted to the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[O:32]=[S:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1
Reactant: O=S1(=O)CCCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 90.2 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 211 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (415 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[Na].[CH3:31][S:32]([OH:34])=[O:33]>CC(C)=O>[Cl:28][C:20]1[CH:19]=[C:18]([C@@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:25])=[O:26]
Reactant: CS(=O)O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CS(=O)(=O)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 30, 102.2 mg, 0.20 mmol) in acetone (1 mL) was cooled to 0° C. and then treated with the sodium salt of methanesulfinic acid (31.8 mg, 0.30 mmol). The reaction stirred at 0° C. for 1 h and then at 25° C. for 4 h 20 min. A second aliquot of the sodium salt of methanesulfinic acid (24.0 mg, 0.24 mmol) was added, and the reaction was stirred at 25° C. overnight. The reaction was then concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (2×25 mL) and a saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfonylmethyl-pyrazin-2-yl)-propionamide (74.9 mg, 73%) as a white foam: mp 91–95° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O5S2 (M+H)+ 500.1075, found 500.1080.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:16][CH3:17])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>CN(C)C=O>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccccc1O
Reactant: BrCc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1ccc2ccccc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
3.9 g (35 mmol) of potassium tert-butoxide were added a little at a time to 5 g (33 mmol) of methyl salicylate in 200 ml of dimethylformamide). After about 15 min, 7.3 g (33 mmol) of 2-(bromomethyl)naphthalene were added and the reaction mixture was heated to 100° C. for about 3 h. The reaction mixture was then poured into ice-water and the product was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. 9.15 g (95%) of the product were obtained.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[I:15]I>C1COCC1.O.CCOCC>[CH2:1]([C@@H:8]1[CH2:12][C@H:13]([CH2:14][I:15])[O:10][C:9]1=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CC[C@@H](CCCCCCC)C(=O)O
Reactant: II
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC[C@@H]1C[C@H](CI)OC1=O
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a solution of 7.14 g (0.036 mol) of the product of Example 5 in 750 mL of THF/H2O (2:1), cooled to 0 degrees, was added 7.22 g (0.072 mol) of KHCO3 followed by 11.97 g (0.072 mol) of KI and then 18.30 g (0.072 mol) of iodine. The reaction was allowed to warn to room temperature and stirred for 18 h. The resulting mixture was diluted with ether and the organic layer was washed with aqueous sodium bisulfite solution, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 8.30 g (71%) of the title compound and 3.36 g (29%) of the corresponding iodo-trans lactone as white solids. CI Mass Spec: 325.3 (M+H).
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([F:16])[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:36][C:34]([F:35])([F:37])[C:26]1[CH:25]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:15][C@:14]3([C:17]([O:19][CH2:20][CH3:21])=[O:18])[F:16])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1
Reactant: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@]1(F)C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.4 %

Procedure:
A mixture of ((1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-ethoxycarbonyl-6-fluoro-1-phenyl-8-azabicyclo[3.2.1]octane (Example 170; 52 mg, 0.085 mmol), 10% palladium on charcoal (123 mg), ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 40 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (13 mg, 30%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=O)C.[Li+].[BH4-].C1COCC1.[NH4+].[Cl-]>C1COCC1>[OH:3][CH2:4][C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[C:25]([CH3:26])[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccccc2C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(CO)Cc2ccccc2C1
Temperature: 100 °C
Yield: 82.3 %

Procedure:
To a solution of 2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (80 mg, 0.21 mmol) in anhydrous THF (1 mL) is added dropwise 2M LiBH4/THF (0.84 mL, 1.68 mmol) at RT under argon. The resulting solution is heated for 20 min at 100° C. on microwave. After cooling to room temperature, the reaction solution is poured into ice-water and aq. NH4Cl saturated solution to reach pH 7. The solution is extracted with EtOAc (50 mL×3). The combined EtOAc phase is washed with brine (10 ml×2), dried over Na2SO4 and concentrated. The residue is purified by HPLC to give a pure product (230) as white solid (58 mg, 82%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[OH-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:12]2([CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:16]=1
Reactant: ClCc1cccnc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: c1cncc(CC2(Cc3cccnc3)c3ccccc3-c3ccccc32)c1

Procedure:
The title compound was prepared following the procedure described in Example 5 from 10.0 mmole of fluorene, 22.0 mmole of 3-picolylchloride hydrochloride, 2.0 mmole of cetyl tri-n-butyl phosphonium bromide, 20 ml of 50% sodium hydroxide and 40 ml of toluene by reaction at 50° for 6 hrs. The material was chromatographed (silica, CH2Cl2 /MeOH,95:5) to yield 2.6 g (70%), m.p. 137°-138°. δ: 3.41(s,4H), 6.71-6.97(m, 4H), 7.17-7.35(tt,6H), 7.50-7.54(d,J=6.9Hz,2H), 7.91(s,2H), 8.12-8.15(d,J=5.4Hx,2H), HRMS calculated for C25H20N2 : 348.1632 Found: 348.1626
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].Br[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[O:24]1>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25](=[O:26])[O:24]2)=[O:19])[CH2:15]1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: O=C1OC(Br)c2ccccc21
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@H]1OC(=O)c2ccccc21
Yield: 41.2 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 640 mg) and 3-bromophthalide (456 mg) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(3-oxo-1,3-dihydroisobenzofuran-1-yl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-17-1, 380 mg) as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([CH:40]([CH3:42])[CH3:41])=[CH:35][C:34]=1B(O)O.[OH-].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:21]=3[C:34]3[CH:35]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:37]([F:39])=[CH:38][C:33]=3[Cl:32])[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ccc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reactant: CC(C)c1cc(B(O)O)c(Cl)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: CSc1ccc(-c2cc(C(C)C)c(F)cc2Cl)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzyl]-4-methyl-1,3-oxazolidin-2-one (60 mg, 0.114 mmol) in 1,4-dioxane (1 mL) was added (2-chloro-4-fluoro-5-isopropylphenyl)boronic acid (10 mg, 0.12 mmol), [1,1′-bis(diphenylphosphino) ferrocene] dichloropalladium (II) (28 mg, 30 mol %) and aqueous potassium hydroxide (95 μL, 3M, 2 eq.). The reaction mixture was purged with nitrogen and then sealed in a microwave vessel. The reaction vessel was subject to microwave irradiation at 150° C. for 30 min. Crude mixture was worked up with water and EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product. This was purified by preparative TLC plate to afford the titled compound. LC-MS: 619.95 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.83-7.88 (m, 1H), 7.72 (s, 1H) 7.68 (s, 1H), 7.30-7.35 (m, 1H), 7.24-7.29 (m, 1H), 7.11-7.19 (m, 2.5H), 7.04-7.07 (m, 0.5H), 5.62 (d, J=8.2 Hz, 0.5H), 5.24 (d, J=8.0 Hz, 0.5H), 4.87 (d, J=15.3 Hz, 0.5H), 4.70 (d, J=15.8 Hz, 0.5H), 3.79-3.98 (m, 2H), 3.18 (m, 1H), 2.55 (s, 1.5H), 2.54 (s, 1.5H), 1.20-1.29 (m, 6H), 0.53 (d, J=6.4 Hz, 1.5H), 0.47 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.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]>[CH3:12][O:11][C:4]1[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=[C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)[CH:3]=1
Reactant: COc1cc(Br)cn2nccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2nccc12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (500 mg, 2.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (916 mg, 4.40 mmol), tris(dibenzylideneacetone)dipalladium (0) (101 mg, 0.110 mmol), potassium fluoride (422 mg, 7.27 mmol), and tri-t-butylphosphonium tetrafluoroborate (63.9 mg, 0.220 mmol) were suspended in DMF (22 ml), sparged with argon for 10 minutes, then heated to 100° C. After 2.5 h, the mixture was cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>O>[CH3:1][O:2][C:3]([CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:29][C:30]([OH:32])=[O:31])[C:6]1=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CN1Cc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask are treated with dry DMF. Tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for one hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent concentrated in vacuo. The title compound is obtained as brown viscous oil crystallizing on standing. [M+H]+ 335.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[C:28]([CH3:35])[N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:31]4[C:26]([O:25][CH3:24])=[N:27][C:28]([CH3:35])=[CH:29][CH:30]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: COc1nc(C)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(C)ccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Yield: 54.9 %

Procedure:
To 80 mg (0.217 mmol) of (S)-isopropyl(1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate in a microwave vial was added, 54 mg (0.326 mmol) of (2-methoxy-6-methylpyridin-3-yl)boronic acid, 92 mg (0.435 mmol) of K3PO4, 18 mg (0.022 mmol) PdCl2(dppf)2, 3 mL of DME and then 1 mL water. The resulting mixture was microwaved at 140° C. for 0.5 hr. It was diluted with EtOAc, washed with brine, and the organic layer was dried over MgSO4. It was concentrated and purified on the neutral PREP HPLC to obtain 50.6 mg of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6H) 2.13-2.31 (m, 2H) 2.53 (s, 3H) 2.89 (s, 3H) 3.43 (dd, J=10.61, 7.07 Hz, 1H) 3.49-3.56 (m, 1H) 3.70-3.76 (m, 2H) 4.06 (s, 3H) 4.99 (m, 2H) 6.61 (d, J=9.85 Hz, 1H) 6.89 (d, J=7.83 Hz, 1H) 7.79 (d, J=9.85 Hz, 1H) 8.12 (s, 1H) 8.69 (d, J=7.83 Hz, 1H). LRMS (ESI) m/e 425 [(M+H)+, calcd for C22H28N6O3 424].
Reaction SMILES: CC1C=CN=C(C=O)C=1.[CH2:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:11]
Reactant: CCc1ccnc(CO)c1
Agent: Cc1ccnc(C=O)c1
Product: CCc1ccnc(C=O)c1
Yield: 84.2 %

Procedure:
In a manner similar to that described for the preparation of 4-methyl-2-pyridine-carboxaldehyde, 4-ethyl-2-hydroxymethylpyridine (1.60 g, 11.68 mmol) yielded 1.33 g (84%) of 4-ethyl-2-pyridinecarboxaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5](O)[C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:2]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Cc1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To a magnetically stirred solution of hydroxy-[2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13b (0.72 g, 2.11 mmol) in DCM (21 mL) under Ar atmosphere was added P2I4 (0.84 g mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 4 h. Aqueous NaH2CO3 (100 mL) was added, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic layers were washed with water (100 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.29 g, 42%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.3 Hz, 3H), 2.33 (s, 3H), 3.82 (s, 3H), 3.96 (s, 2H), 4.19 (q, J=7.3 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.85 (s, 1H).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH3:6][C@H:7]1[CH2:16][CH:15]=[CH:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C@H:8]1[C:17]([O:19]CC)=O.Cl.CC([O-])(C)C.[K+]>C1COCC1.CN(C=O)C.CC1C=CC(S(O)(=O)=O)=CC=1.O.O>[CH3:6][C@H:7]1[CH2:16][CH:15]=[CH:14][C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[C@H:8]1[C:17](=[O:19])/[CH:1]=[CH:2]/[CH3:3]
Reactant: CCOC(=O)[C@H]1[C@@H](C)CC=CC12CCCC2
Reactant: C=CC[Mg]Cl
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C/C(=O)[C@H]1[C@@H](C)CC=CC12CCCC2
Temperature: 20 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
At 5° C., a solution of allylmagnesium chloride (12.1 ml, 2 M in THF) was treated dropwise with a solution of rel-(6S,7S)-ethyl 7-methylspiro[4.5]dec-9-ene-6-carboxylate (1.5 g, 6.7 mmol, prepared as described in Example 19) in THF (20 ml), stirred at 20° C. for 1 h, poured into cold 2N aqueous HCl (30 ml), and extracted twice with MTBE (70 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (100 ml), dried (MgSO4), and concentrated. The crude product (1.9 g) was dissolved in DMF (10 ml) and added to a solution of KOt-Bu (1.2 g, 10.7 mmol) in DMF (10 ml). The resulting mixture was stirred for 1 h, poured into cold 2N aqueous HCl (30 ml), and extracted twice with hexane (80 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (100 ml), dried (MgSO4), and concentrated. The crude product (1.9 g) was then dissolved in toluene (15 ml) and treated with PTSA.H2O (15 mg, 0.077 mmol). The resulting solution was stirred at 60° C. for 2.75 h, poured into cold water (30 ml), and extracted with cyclohexane (20 ml). The combined organic phases were washed with a saturated aqueous solution of NaCl (20 ml), dried (MgSO4), and concentrated. FC (120 g SiO2, hexane/MTBE 25:1) of the crude product (1.38 g) gave (E)-1-(rel-(6S,7S)-7-methylspiro[4.5]dec-9-en-6-yl)but-2-en-1-one (0.63 g, 43%). Boiling point: 115° C. (0.09 mbar).