Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.O1CCCC1.C(N(CC)CC)C.[CH3:32][C:33]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[O:9][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOc1ccc(C(O)c2cc(Br)ccc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a suitable reaction flask was charged (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanol (2.93 mmoles; 1.00 g) and tetrahydrofuran (122.89 mmoles; 10.00 mL; 8.86 g) to afford a clear solution. Triethylamine (3.81 mmoles; 0.530 mL; 385.06 mg) was then added via syringe, followed by tert-butyl dimethylsilyl trifluoromethanesulfonate (3.81 mmoles; 0.875 mL; 1.01 g) at room temperature. The reaction was allowed to stir at room temperature until completion (as determined by GCMS analysis). To the reaction mixture was then added deionized water (10 mL) and ethyl acetate (20 mL). The layers were shaken together, allowed to settle and then were separated. The organic phase was washed with saturated aqueous sodium chloride (10 mL) and then was dried over magnesium sulfate, filtered and concentrated to provide the crude product (1.45 g). The crude oil was purified by flash chromatography on silica gel eluting with a gradient of 0 to 5% ethyl acetate in hexanes to afford 1.00 g of product as a clear oil (75% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:21][C:18]1([CH3:22])[O:17][CH2:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:20][O:19]1
Reactant: CC1(C)OCC(c2ccc(OCc3ccccc3)cc2)CO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)OCC(c2ccc(O)cc2)CO1
Temperature: 30 °C
Yield: 37.2 %

Procedure:
To a suspension of 10% Pd/C (85 mg) in methanol was added a solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-1,3-dioxane (850.0 gm, 0.00775 moles) in methanol (20 ml). To this was added ammonium formate (900 mg, 0.0143 mole) and the reaction mixture was refluxed for 2 hrs. The reaction mixture was then cooled to 30° C. and filtered through celite. The filtrate was evaporated under reduced pressure and residue was dissolved in dichloromethane and filtered through celite. The filtrate was evaporated under reduced pressure to yield 600 mg product as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:27]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CO[Si](C)(C)C(C)(C)C)n2Cc2ccccc2)n1
Temperature: 105 °C

Procedure:
A flask was charged with 1-benzyl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.25 g, 0.65 mmol, from Step 3), di-tert-butyl hydrazine-1,2-dicarboxylate (0.15 g, 0.65 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (51 mg, 0.065 mmol), Cs2CO3 (0.210 g, 0.646 mmol) and toluene (2.1 mL). The mixture was degassed by a stream of nitrogen through the solution. The mixture was then sealed and heated to 105° C. for 70 minutes. The reaction was diluted with DCM, filtered and concentrated. Purification via flash chromatography, eluting with a gradient from 0-10% EtOAc in hexanes afforded product as a white solid (0.20 g, 53%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10](=[CH2:17])[C:11]([O:13][CH2:14][CH2:15][NH2:16])=[O:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>C(#N)C>[CH3:17][C:10](=[CH2:9])[C:11]([O:13][CH2:14][CH2:15][NH:16][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[O:12]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
In a 1-liter three-neck flask equipped with a thermometer, a reflex condenser and a calcium chloride tube were placed 350 g of acetonitrile, 70.7 g (0.699 mol) of triethylamine, 33.1 g (0.200 mol) of 2-aminoethyl 2-methylacrylate hydrochloride and 0.2 g of phenothiazine, followed by cooling to −30o C with stirring. After the inside temperature of the flask reached −30° C., 40.3 g (0.239 mol) of trifluoromethanesulfonyl chloride was introduced as a gas into the slurry over 1 hour. Upon completion of the gas introduction, the reaction solution was stirred for 1 hour and then warmed to room temperature. The solvent (acetonitrile) and the unreacted reaction substrate (trifluoromethanesulfonyl chloride) were evaporated from the reaction solution under a reduced pressure. To the solution was added 1 liter of diisopropyl ether. The resulting slurry was subjected to filtration to filter out a precipitate of triethylamine hydrochloride. The filtrate was washed three times with 200 g of 10% aqueous sodium chloride solution, and then, dried with 40 g of magnesium sulfate. The magnesium sulfate was removed by filtration. After that, 0.2 g of phenothiazine was added to the organic phase. The solvent was evaporated to obtain 22.5 g of a crude reaction product. The crude reaction product was subjected to distillation under a reduced pressure, thereby yielding 9.9 g of target 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate as an organic fraction at 105-115° C. /13Pa. The purity of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was determined by gas chromatography to be 98.0%. The yield of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was 19%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:28][NH:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Yield: 51.4 %

Procedure:
To a 100 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (2.02 g, 7.5 mmol) followed by a addition of anhydrous THF (60 mL) under an atmosphere of nitrogen. Benzhydrazide (1.02 g, 7.5 mmol) was subsequently added and the mixture was cooled to −15° C. To this mixture was added HOBt (1.02 g, 7.5 mmol) followed by addition of EDC (2.88 g, 15.0 mmol) and lastly, TEA (3.2 mL, 23 mmol) was slowly added. The temperature of this reaction was maintained between −25° C. and −15° C. for a period of 1 h then allowed to warm to room temperature overnight. The solids were filtered off and washed with additional THF (20 mL) and EtOAc (20 mL). The mother liquor was then diluted with EtOAc (200 mL) and washed with 5% citric acid/water (2×50 mL), saturated sodium bicarbonate (1×25 mL), and brine (1×50 mL) then dried over sodium sulfate. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a white solid. This was purified via silica gel chromatography eluted with 85% EtOAc/hexane to provide title compound as a white solid (1.49 g, 51%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.64 (br s, 2H), 7.94 (m, 2H), 7.60 (m, 1H), 7.51 (m, 3H), 6.73 (d, J=8.7 Hz, 1H), 5.59 (d, J=7.2 Hz, 1H), 4.71 (br s, 1H), 4.24 (m, 1H), 4.12 (dd, J=5.1, 7.3 Hz, 1H), 2.35 (s, 3H), 1.39 (d, J=6.3 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[N:11]=[CH:12][S:13][C:14]=1[CH:15]=O)(=[O:9])=[O:8].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:14]2[S:13][CH:12]=[N:11][C:10]=2[S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: O=Cc1scnc1S(=O)(=O)c1ccccn1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 4-(pyridine-2-sulfonyl)thiazole-5-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)C>CN1C(=O)CCC1>[N+:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cccc(Nc3ccc(CC(=O)O)cc3[N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a suspension of 1i (3.0 g, 15.1 mmol) in anhydrous NMP (2 ml) was added 2c (2.88 g, 15.1 mmol) and triethylamine (2.1 ml, 30.2 mmol). The mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was poured into a mixture of diethyl ether and petroleum ether (100 ml, 1:1 v/v) resulting in separation of an oily lower phase. The mixture was decanted and the oil was dissolved in dichloromethane and eluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v) to yield 3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid (1.63 g, 29%). This acid (0.64 g, 1.73 mmol) was dissolved in methanol and concentrated hydrochloric acid (0.2 ml) was added. The mixture was heated to reflux for 4 days. The solvent was removed under reduced pressure and the residue was purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent to leave the ester (0.47 g, 71%) as a red oil. This oil was hydrogenated in methanol at ambient pressure using Pd (5% on activated carbon) as the catalyst to yield the corresponding diamine (0.38 g). This diamine was treated with triethyl orthoformate (0.35 ml, 2.14 mmol) and a catalytic amount of pTSA in THF (5 ml) at 80° C. for 30 min. The solvent was evaporated and the residue was partitioned between aqueous sodium hydroxide (1M) and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and eluted through a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v). The product precipitated as the hydrochloride by addition of a solution of anhydrous hydrogen chloride in diethyl ether to the eluate. Yield of 4I1: 0.2 g (41%). M.p. 140-142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[C:29]([F:35])[N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[F:35][C:29]1[N:28]=[C:27]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:32]=[CH:31][C:30]=1[CH2:33][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: Fc1cnc2[nH]ccc2c1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(F)cc34)c(F)n2)cn1
Yield: 8.7 %

Procedure:
In a round bottom flask, 5-fluoro-1H-pyrrolo[2,3-b]pyridine (155, 0.115 g, 0.845 mmol) was combined with (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (156, 0.397 g, 1.10 mmol), 2.60 mL of acetonitrile, trifluoroacetic acid (0.325 mL, 4.22 mmol) and triethylsilane (0.810 mL, 5.07 mmol) and the reaction was heated to reflux for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-1622, 28 mg). MS (ESI) [M+H+]+=382.1.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][C:14]4=[C:13](I)[C:12]=3[CH:11]=2)[CH2:8][CH2:7]1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>CCCCCC.O1CCCC1>[C:23]([O:27][C:28](=[O:29])[NH:30][C@@H:34]([CH3:33])[CH2:35][C:13]1[C:12]2[CH:11]=[C:10]([O:9][CH:6]3[CH2:8][CH2:7]3)[CH:18]=[CH:17][C:16]=2[N:15]2[CH2:19][CH2:20][CH2:21][C:14]=12)([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: Ic1c2n(c3ccc(OC4CC4)cc13)CCC2
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](Cc1c2n(c3ccc(OC4CC4)cc13)CCC2)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
37.4 mL of a 1.6 M solution of n-butyllithium in n-hexane was added at −78° C. dropwise during 10 min to a solution of 18.65 g 6-cyclopropoxy-8-iodo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene in 250 mL tetrahydrofuran. The mixture was stirred at −78° C. for 30 min. 15.55 g (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added to the resulting suspension and the mixture stirred at −78° C. for 30 min and at 0° C. for 45 min. The reaction mixture was distributed between ice-cold 10% citric acid and ethyl acetate. The phases separated, the organic phase washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with hexane: ethyl acetate=4: 1 to yield 11.91 g (S)-[2-(6-cyclopropoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]inden-8-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester as beige crystals melting at 83-84° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:7]=12
Reactant: BrCC1CC1
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: Cc1c(C)n(CC2CC2)c2c(Cl)nccc12
Yield: 92 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and (bromomethyl)cyclopropane, the titled compound was obtained as a white solid. (Yield: 92%)
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C(N1CCNCC1)CC1C=CC=CC=1.Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([O:33][CH3:34])=[C:28]([F:35])[CH:27]=1.[O:36]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[O:39][CH2:38][CH2:37]1>>[F:32][C:31]1[CH:30]=[C:29]([O:33][CH3:34])[C:28]([F:35])=[CH:27][C:26]=1[N:43]1[CH2:44][CH2:45][C:40]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:41][CH2:42]1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: C1CC2(CCN1)OCCO2
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: COc1cc(F)c(N2CCC3(CC2)OCCO3)cc1F
Yield: 31.9 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-phenethylpiperazine were replaced with 4-bromo-2,5-difluoroanisole (1.115 g) and 1,4-dioxa-8-azaspiro[4,5]-decane (859 mg), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=3:1) to provide 8-(2,5-difluoro-4-methoxyphenyl)-1,4-dioxa-8-azaspiro[4,5]decane (455 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].[F:10][CH:11]([F:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>>[F:10][CH:11]([F:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc(I)ccc1F
Reactant: C#Cc1ccc(OC(F)F)cc1
Product: Cc1cc(C#Cc2ccc(OC(F)F)cc2)ccc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Fluoro-4-iodo-2-methyl-benzene (0.125 g, 0.53 mmol), and 1-Difluoromethoxy-4-ethynyl-benzene (0.09 g, 0.53 mmol), and was obtained as a yellow semi solid, (0.141 g, 96%), and identified by NMR and mass spectral analyses. MS (EI+): 276 (M+).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([OH:18])=[O:17].CN(C=O)C.CCN(C(C)C)C(C)C>C(N(CC)CC)C.C(OCC)(=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: C#Cc1cnc2cnccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)cc1C#Cc1cnc2cnccn12

Procedure:
can be prepared in a manner similar to that described above for the Sonogashira reaction. 3-Ethynylimidazo[1,2-a]pyrazine and 3-iodo-4-methylbenzoic acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by triethylamine. The product can be isolated by filtration of the crude reaction mixture. The filter cake is washed sequentially with a solvent such as ethyl acetate and then water, then dried in a vacuum oven. Further purification can be achieved by slurrying the solids in water adjusted to pH 3 with the addition of concentrated HCl. After filtration and water wash, the product can be dried in a vacuum oven.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][CH:3]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1nc(C(F)(F)F)ccc1Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Temperature: 80 °C

Procedure:
(5-Bromo-pyridin-2-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-amine (290 mg, 0.87 mmol) and {4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (312 mg, 0.87 mmol) were dissolved in anhydrous DME (3 mL) in a pressure vessel. PdCl2dppf (21 mg, 0.026 mmol) was added, followed by aqueous sodium carbonate (2M, 0.870 mL, 1.74 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and heated at 80° C. for 18 hours. The mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (7-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) ppm 1.08-1.21 (m, 2 H) 1.50 (td, J=12.44, 10.23 Hz, 2 H) 1.81 (m, 4 H) 2.25 (d, J=6.57 Hz, 2 H) 2.59 (s, 3 H) 3.60 (s, 3 H) 7.22 (d, J=8.59 Hz, 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.57 (d, J=8.34 Hz, 2 H) 7.66 (d, J=8.59 Hz, 1 H) 7.97 (dd, J=8.59, 2.53 Hz, 1 H) 8.48 (d, J=2.53 Hz, 1 H) 8.64 (s, 1 H) 8.66 (d, J=8.34 Hz, 1 H); MS (M+H)+ 484.3.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][C@H:18]2[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:13]1=[O:36])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][C@H:18]2[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:13]1=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(C)(=O)=O)C1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (835 mg) in MeOH (5 mL) was charged with 10% Pd/C, Degussa (800 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 2 h and then filtered and concentrated to afford tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (566 mg). MS found: (M+H)+=390.3.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11][CH:10]=1)=[O:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[N:11]1[CH:10]=[C:9]([CH2:7][OH:8])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=12
Reactant: O=Cc1cnc2n1CCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc2n1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a suspension of aluminum lithium hydride (0.40 g) in THF (30 ml), 3-formyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.48 g) in. THF (50 ml) was added dropwise at 0° C. The mixture was stirred for 1 hour at 0° C., and water (0.4 ml), 15% aqueous solution of sodium hydroxide (0.4 ml) and water (1.2 ml) were added dropwise to the mixture. The mixture was stirred at room temperature for 18 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration. The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether, to give 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-methanol (1.24 g) as colorless crystals.