Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:14])=[O:13])[CH:8]=2)[O:3]1.Br[CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1>C(#N)C>[C:29]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10]3)(=[O:14])=[O:13])[CH:28]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: BrCc1cccc(-c2ccccc2)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(Cc1cccc(-c2ccccc2)c1)S(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Yield: 89 %

Procedure:
To a solution of tert-butyl 2-(2,2-dimethylchroman-6-sulfonamido)acetate (20 mg, 0.056 mmol) in acetonitrile (1 mL) was added 3-(bromomethyl)biphenyl (19.47 mg, 0.079 mmol) and resin-supportedBEMP (42.9 mg, 0.084 mmol). The mixture was heated in an oil bath at 90° C. overnight. The reaction mixture was filtered, and the filtrate was concentrated to give an orange residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate as an oil (26 mg, 84% yield). 1H NMR (500 MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.54-7.49 (m, 3H), 7.44-7.40 (m, 3H), 7.38 (dd, J=9.4, 5.8 Hz, 1H), 7.33 (ddd, J=6.7, 4.0, 1.2 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 4.57 (s, 2H), 3.84 (s, 2H), 2.78 (t, J=6.7 Hz, 2H), 1.80 (t, J=6.7LRMS [ESI, MNa+] m/z calcd for C30H35NO5SNa 544.21. found 544.32. To the solution of tert-butyl 2-(N-(biphenyl-3-ylmethyl)-2,2-dimethylchroman-6-sulfonamido)acetate (23 mg, 0.044 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.102 mL, 1.323 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated to give a reddish residue, which was purified by preparative HPLC using MeCN—H2O-0.1% TFA as the solvent to obtain the product as a white powder (17 mg, 82% yield). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.41 (dd, J=13.4, 5.5 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.87-6.83 (m, 1H), 4.52 (s, 2H), 3.97 (s, 2H), 2.77 (t, J=6.7 Hz, 2H), 1.79 (t, J=6.7 Hz, 2H), 1.33 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C26H26NO5S 464.15, found 464.32.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH:7]=S(C)C)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13](=[O:16])[CH:14]=[CH2:15]>ClCCl>[C:1]([O:5][C:6]([C@@H:7]1[CH2:15][C@H:14]1[C:13](=[O:16])[CH3:12])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)=O
Reactant: CS(C)=CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)[C@@H]1C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (dimethyl-λ4-sulfanylidene)-acetic acid tert-butyl ester (6.3 g, 35.7 mmol) (CAS 195453-96-4; K. Saigo et al., J. Org. Chem. 2006, 71, 1633-1639) in dichloromethane (36 ml) was treated dropwise at 15° C. with but-3-en-2-one (2.64 g, 3.1 ml, 35.7 mmol) keeping the internal temperature below 27° C. The yellow mixture was stirred overnight at room temperature. For the workup, all volatiles were evaporated to give a yellow oil. The crude oil was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The (1R,2R)-rel-2-acetyl-cyclopropanecarboxylic acid tert-butylester was obtained as a colorless oil (5.48 g, 83% yield). MS (ISP): m/z=185.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Br.Br[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: BrCc1cccnc1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Agent: Br
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16]>>[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH:16][C:1](=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)CN
Reactant: CCCC(CCC)C(=O)Cl
Agent: Cl
Product: CCCC(CCC)C(=O)NCC(=O)OC

Procedure:
The title compound was prepared from valproyl chloride (19.34 g, 119 mmole) and glycine methyl ester hydrochloride (15.0 g, 119 mmole), according to the procedure described in Ex. 4.22 g (102 mmole, 86%) of an off-white solid, mp 68° C., was thus obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]2[NH:26][CH:27]=[C:28]([NH:29][C:30](=[O:35])[C@H:31]([O:33][CH3:34])[CH3:32])[C:17]=12>CCCCO.O>[CH3:34][O:33][C@H:31]([CH3:32])[C:30]([NH:29][C:28]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:22]([F:25])([F:23])[F:24])[C:16]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:26][CH:27]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Solvent: O
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 41 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (456 mg, 2.28 mmol) and N,N-diispropylethylamine (294 mg, 0.396 mL, 2.28 mmol) were added to a suspension of (R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (244 mg, 0.759 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube under a nitrogen atmosphere at 160° C. for 24 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give tert-butyl (R)-1-(3-((R)-2-methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (151 mg, 41%) as a solid. LCMS (APCI+) m/z 386.1, 486.1 (M+H)+, Retention time=3.85 minutes.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([O:12][C:13]([NH:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:24][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:22]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C=O)C>C(#N)C>[C:8]([O:12][C:13]([NH:15][N:16]1[C:20]([C:6]#[N:5])=[CH:19][CH:18]=[C:17]1[CH:21]1[CH2:22][N:23]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:24]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nn1cccc1C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1c(C#N)ccc1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
A solution of chlorosulfonylisocyanate (541 μL, 6.22 mmol) in acetonitrile (5 mL) was added dropwise to a cooled (0° C.) solution of benzyl 3-{1-[(tert-butoxycarbonyl)amino]-1H-pyrrol-2-yl}azetidine-1-carboxylate (2.10 g, 5.65 mmol) in acetonitrile (15 mL). The mixture was stirred at 0° C. for 30 min and was warmed to rt. After 1 h, the mixture was recooled (0° C.) and DMF was added dropwise. The reaction was allowed to warm to rt. After 30 min, the mixture was poured onto crushed ice (100 g) and was allowed to warm to rt. The aqueous mixture was extracted with EtOAc (3×75 mL) and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to obtain 800 mg (36%) of the desired product, which was used without further characterization.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH:37](I)[CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:37]([O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])[CH:38]([CH3:40])[CH3:39])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)C(I)OC(=O)OC1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)C(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 15.9 %

Procedure:
In the same manner as in Example 81, 84 mg of the title compound was prepared from 367 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 300 mg of 1-(cyclohexyloxycarbonyloxy)-2-methylpropan-1-yl iodide.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C6CCCCO6)[CH:24]=5)=[CH:18][N:19]=[C:14]4[N:13]=[N:12]3)=[CH:9][C:4]2=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)Cl>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([C:20]5[CH:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[CH:24]=5)=[CH:18][N:19]=[C:14]4[N:13]=[N:12]3)=[CH:9][C:4]2=[CH:3][CH:2]=1
Reactant: c1cc2cc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)ccn2n1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: OCCn1cc(-c2cnc3nnn(Cc4ccn5nccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine 311-a (10 mg, 0.022 mmol) (prepared according to the procedure of Compound 1) in CHCl3 was added NBS (4.4 mg, 0.025 mmol). The reaction mixture was stirred at rt for 1 h, then concentrated. The resulting residue was dissolved in CHCl3 (2 mL) and MeOH (2 mL), followed by the addition of 6N HCl in MeOH. The resulting mixture was stirred for 30 min, then treated with NH3.H2O to bring pH to 8. The mixture was concentrated and purified by prep-TLC to afford the title compound. MS (m/z): 439.9 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].FC1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=O)C1=O.[B].C(OC(=O)NCC1C=C2C=CNC2=NC=1)(C)(C)C>>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: CC(C)(C)OC(=O)NCc1cnc2[nH]ccc2c1
Agent: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: [B]
Product: NCc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-aminomethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and (1H-Pyrrolo[2,3-b]pyridin-5-ylmethyl)-carbamic acid tert-butyl ester as substituted bicyclic heterocycle to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.034 (s, 1H) 10.051 (t, J=5.9 Hz, 1H) 8.437 (s, 1H) 8.393 (d, J=6.8 Hz, 1H) 8.334 (s, 1H) 8.230 (d, J=6.5, 1H) 8.096 (s (br), 2H) 7.917 (m, 1H) 7.687 (s, 1H) 7.630 (d, J=7.8 Hz, 1H) 7.455-7.345 (m, 3H) 7.217 (d, J=7.5 Hz, 1H) 7.169-7.119 (m, 1H) 6.596 (t, J=6.8 Hz, 1H) 5.194 (s, 2H), 4.583 (d, J=5.5 Hz, 2H) 4.209-4.142 (m, 2H); MS m/z=500.10 M+H.
Reaction SMILES: Cl.C([N:4]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][C:7](=[CH2:15])[CH2:6][CH:5]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=O>C(O)C>[CH2:15]=[C:7]1[CH2:6][CH:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:4][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8]1
Reactant: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)C1
Agent: Cl
Solvent: CCO
Product: C=C1CC(C(=O)OCC)NC(C(=O)OCC)C1
Yield: 79.7 %

Procedure:
1.5 ml of 12N hydrochloric acid were added to a solution of 2.8 g of the product of Step C of Example 5 and 30 ml of ethanol and the reaction mixture was refluxed for 2 hours. After evaporation to dryness, the residue was taken up in ethyl acetate and washed with 10% sodium bicarbonate. The organic phase was dried, filtered and evaporated to dryness to obtain 2.0 g of product which was purified on silica eluting with a cyclohexane-ethyl acetate (8-2) mixture to obtain 0.730 g of the cis product and 0.980 g of the trans product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:22])[C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1)=[O:13].[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:22])[C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1)([OH:13])[C:24]([F:26])([F:25])[F:23]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C(C)C(=O)c2ccc(=O)n(C)c2)c(Cl)c1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1Cl

Procedure:
In analogy to Example 165, step 3, 5-[2-(2,3-dichloro-4-methoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion.)=408.2 [M−H+].
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH2:12][C:13]#[N:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.N.[N-]=[N+]=[N-].[Na+].[Na].[Cl-].[NH4+]>>[O:9]1[C:5]2[CH:4]=[C:3]3[CH2:11][CH:12]([C:13]#[N:14])[C:2]3=[CH:10][C:6]=2[O:7][CH2:8]1
Reactant: N#CCCc1cc2c(cc1Br)OCO2
Agent: N
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Product: N#CC1Cc2cc3c(cc21)OCO3
Reaction time: 0.5 h

Procedure:
46 g of 3-(6-bromo-1,3-benzodioxol-5-yl)propanenitrile are introduced in portions into 1.4 liters of liquid ammonia in which there is dissolved sodium azide which was prepared previously by the introduction of 16.7 g of sodium into the liquid ammonia. After 30 minutes' contact, the reaction mixture is treated with 38.7 g of ammonium chloride, and then the ammonia is distilled off at room temperature. The residue is taken up in ether and filtered; the precipitate is washed with ether. The combined ethereal phases are evaporated and the resulting residue is recrystallised from isopropyl alcohol, enabling the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:18][OH:19])[CH3:2].[H][H]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:18][OH:19])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Palladium on carbon (10 wt. %, 15 mg) was added to a solution of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester (290 mg, 1.02 mmol) in EtOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 3 h. The reaction mixture was filtered through celite, washing with EtOH, and the filtrate was concentrated in vacuo to afford 295 mg (quant. crude) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[N:10]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)sc1C
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)sc1C
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
(5-(4,5-dimethyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione) (Prep 15, 100 mg) suspended in Pyridine (2 mL) was slowly added to a stirring solution of benzoyl chloride (0.156 ml, 1.344 mmol) in Pyridine (1 mL) under nitrogen atmosphere. The resulting yellow solution was stirred at rt for 5.5 hours. Water was added (3 mL) and the mixture was extracted with EtOAc (10 mL). The organic was washed with NH4Cl saturated aqueous solution (2×2 mL) dried (Na2SO4, vacuo) to afford 340 mg of a yellowish solid that was dissolved in EtOAc (30 mL) and washed with NaHCO3 aqueous saturated solution. The organic was dried (Na2SO4, vacuo) to afford the title compound as a yellowish solid (180 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:38])([F:37])[F:26])=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(-c3ccccc3C(F)(F)F)c2n1
Yield: 91.9 %

Procedure:
Following procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), 2-trifluoromethylphenyl boronic acid (0.1538 g, 0.81 mmol), potassium carbonate (0.1292 g, 0.93 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0360 g, 0.03 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-100% ethyl acetate in hexanes) to give (2S)-benzyl-2-(8-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.264 g, 0.57 mmol, 70%).
Reaction SMILES: FC(F)(F)C1C=C(CO[C@@H]2CC[C@@H]3N[C@@]2(C2C=CC=CC=2)C[C@H]3C2N(CSC3C=CC=CC=3)N=NC=2)C=C(C(F)(F)F)C=1.[F:44][C:45]([F:86])([F:85])[C:46]1[CH:47]=[C:48]([CH2:56][O:57][C@@H:58]2[CH2:64][CH2:63][C@@H:62]3[NH:65][C@@:59]2([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:60][C@H:61]3[C:66]2[N:70]=[N:69][N:68]([CH2:71]SC3C=CC=CC=3)[CH:67]=2)[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1.[BH4-].[Na+]>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[F:55][C:52]([F:53])([F:54])[C:50]1[CH:49]=[C:48]([CH2:56][O:57][C@@H:58]2[CH2:64][CH2:63][C@@H:62]3[NH:65][C@@:59]2([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[CH2:60][C@H:61]3[C:66]2[N:70]=[N:69][N:68]([CH3:71])[CH:67]=2)[CH:47]=[C:46]([C:45]([F:44])([F:85])[F:86])[CH:51]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cn(CSc3ccccc3)nn2)cc(C(F)(F)F)c1
Agent: Cl[Ni]Cl
Agent: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cnnn2CSc2ccccc2)cc(C(F)(F)F)c1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc([C@@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1-phenylthiomethyl-1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane and (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(3-phenylthiomethyl-1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 100; 99 mg, 0.1 mmol) and nickel(II)chloride hexahydrate (233 mg, 1.0 mmol) in methanol (6 ml) and THF (2 ml) at 0° C. was treated with sodium borohydride (112 mg, 2.9 mmol). A black precipitate was formed and the mixture was stirred for 20 minutes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The isomers were separated by preparative TLC eluting with 1:1 ethyl acetate/hexane to afford the title compounds (3-methyl-1,2,3-triazol-5-yl isomer: 17 mg) and (1-methyl-1,2,3-triazol-5-yl isomer: 34 mg), in a combined yield of 61%.
Reaction SMILES: BrBr.[NH:3]1[CH:8]=[CH:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].N1C=CC=NC=1.[OH2:17]>>[OH:17][C:7]1[C:6](=[O:9])[NH:5][C:4](=[O:10])[NH:3][CH:8]=1
Reactant: O
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: BrBr
Solvent: c1cncnc1
Product: O=c1[nH]cc(O)c(=O)[nH]1
Temperature: 0 °C

Procedure:
According to the synthetic method shown in Scheme A, above, bromine is added dropwise to an ice-cooled solution or suspension of a pyrimidine-2,4(1H,3H)-dione derivative of formula (III) in water until the solution or suspension is colored pale yellow. The pyrimidine-2,4(1H,3H)-dione derivatives of formula (III) are prepared, for example, by the methods described in Heterocyclic Compounds 16, The pyrimidine supplement II, D. J. Brown, An Interscience Publication, John Willy & Sons, New York, 1985, Table LVIII, page 728. To the resulting pale yellow solution or suspension is added carefully an ice cold saturated aqueous NaHCO3 solution. The resulting reaction mixture is refluxed, the solvent is removed and the residue is recrystallized from an appropriate solvent or chromatographed over silica-gel to give a 5-hydroxyprimidine-2,4(1H,3H)-dione derivative of formula (IV).