Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:28]=[C:27]([F:29])[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH:30](B1OC(C)(C)C(C)(C)O1)=[CH2:31].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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>[F:29][C:27]1[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=[C:2]([CH:30]=[CH2:31])[CH:28]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(F)c2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 100 °C
Yield: 17.2 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, vinyl boronic acid pinacol ester (97 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a stream of argon. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture was heated in a sealed reaction vessel at 100° C. for 2.5 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((7-fluoro-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (23 mg, 17%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.55 (d, J=6.9 Hz, 2H), 7.23-7.31 (m, 2H), 7.09 (m, 1H), 6.79 (dd, J=11.0, 17.6 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 5.51 (s, 2H), 5.22 (d, J=11.1 Hz, 1H), 4.74 (d, J=4.4 Hz, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.14-1.32 (m, 4H); LCMS (ESI) m/z 423 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=1.C(OC(=O)C)(=[O:18])C>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:18])[CH:10]=1
Reactant: [O-][n+]1ccc(OCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccccn2)cc[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
4-(Pyridin-2-ylmethoxy)pyridine 1-oxide (9.0 g, 45 mmol) was heated to 140° C. in acetic anhydride (100 mL) for 2 h. The solution was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (50 mL) and H2O (50 mL). The resultant black solution was concentrated and the residue was dissolved in hot i-PrOH (40 ml). Et2O (250 mL) was added and the mixture was placed in the freezer for 16 h. The solid was filtered off to provide the title compound (1.9 g, 21%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.13 (br s, 1H), 8.58 (d, J=4.7 Hz, 1H), 7.85 (overlapping ddd, J=7.9, 1.6 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.96 (dd, J=7.3, 2.5 Hz, 1H), 5.76 (d, J=3.4 Hz, 1H), 5.12 (s, 2H).
Reaction SMILES: ClN1C(=O)CCC1=O.Cl[CH2:10][CH2:11][Cl:12].[CH:13]1([CH2:16][NH:17][C:18]2[N:26]=[CH:25]C=C[C:19]=2[C:20]([OH:22])=[O:21])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:12][C:11]1[CH:25]=[N:26][C:18]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15]2)=[C:19]([CH:10]=1)[C:20]([OH:22])=[O:21]
Reactant: ClCCCl
Reactant: O=C(O)c1cccnc1NCC1CC1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cnc1NCC1CC1
Reaction time: 24 h

Procedure:
1-Chloro-2,5-pyrrolidinedione was added at room temperature to a 1,2-dichloroethane and DMF solution of 2-[(cyclopropylmethyl)amino]nicotinic acid, followed by stirring for 1 day. By post-treating the reaction liquid, 5-chloro-2-[(cyclopropylmethyl)amino]nicotinic acid was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[N:12]=[C:13]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][CH2:27]2)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1>CN(C)C=O>[OH:33][CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:13]2[C:14]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][S:17][C:15]=3[N:16]=[C:11]([CH2:10][N:3]3[CH2:7][CH2:6][CH2:5][C:4]3=[O:8])[N:12]=2)[CH2:27][CH2:28]1
Reactant: OCC1CCN(c2nc(CCl)nc3scc(-c4ccccc4)c23)CC1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1nc(N2CCC(CO)CC2)c2c(-c3ccccc3)csc2n1
Reaction time: 0.17 h

Procedure:
Sodium hydride (25 mg, 60% w/w in mineral oil) was added to a solution of 2-pyrrolidinone in dry N,N-dimethylformamide (2 mL) under a nitrogen atmosphere. The mixture was stirred for 10 min then [1-[2-(chloromethyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-4-piperidyl]methanol (100 mg) was added. The mixture was stirred for 2 hr at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (sodium sulfate), filtered and evaporated to give the target compound (96 mg) as a yellow solid. m/z [M+H]+ 424.0. Retention time 3.95 min (LCMS method+ve 6 min). It was used in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][Br:16]
Reactant: COC(=O)c1ccc(C(=O)OC)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(CBr)c1

Procedure:
88 G. of dimethyl-2-methylterephthalate in 1000 ml. of carbon tetrachloride containing 89 g. (1 eq.) of N-bromosuccinimide is refluxed for 3 hours using a heat lamp. The solution is cooled, filtered and evaporated to dryness to give dimethyl-2-bromomethylterephthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH2:8])=[O:7].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH2:8])=[O:7]
Reactant: NC(=O)COc1ccc(C=O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)COc1ccc(CO)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of the product from example 15 step a) (4.4 g) in ethanol (500 ml) was added sodium borohydride (1.56 g) and the mixture allowed to stir for 1 hour. Acidified with glacial acetic acid, evaporated to dryness and extracted into ethyl acetate, washed with water to give the subtitle compound (4.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[N:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: COc1ccc(B(O)O)cn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)nc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxy-5-pyridineboronic acid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[C:28]1(B(O)O)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([C:36]4[C:37]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:33]=[CH:34][CH:35]=4)[C:7]=3[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)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: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2cccc3ccccc23)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1

Procedure:
A mixture of Example 9 (145 mg; 0.37 mmol), 1-naphthylboronic acid (142 mg; 0.82 mmol), cesium carbonate (489 mg; 1.50 mmol) and Pd(PPh3)4 (87 mg; 0.07 mmol) in DMF (4 mL) was stirred at 150° C. for one hour (microwave heating) then concentrated in vacuo. The residue was partitioned between EA and aq. citric acid and the two phases separated. The aqueous layer was dried over magnesium sulfate and concentrated in vacuo. Precipitation from EA/Et2O afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[C:13](=[O:26])[CH2:12]3)[NH:7][C:6]=2[CH:27]=1.C(OC([N:38]1CCN(CC2C=CC(C#N)=CC=2)C(=O)C1)=O)C1C=CC=CC=1.ClC1C=CC2NC(CCl)=NC=2C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]([NH2:38])=[NH:23])=[CH:20][CH:19]=4)[C:13](=[O:26])[CH2:12]3)[NH:7][C:6]=2[CH:27]=1
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reactant: N#Cc1ccc(CN2CCN(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Agent: ClCc1nc2cc(Cl)ccc2[nH]1
Solvent: CO
Product: N=C(N)c1ccc(CN2CCN(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1

Procedure:
Hydrogen chloride gas is bubbled into an ice-cooled solution of 4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-benzonitrile (100 mg, 0.264 mmol), (prepared by deprotecting 4-(4-cyanobenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester, EXAMPLE 66, Part A, followed by alkylation with 6-chloro-2-chloromethylbenzimidazole) in 15 mL of methanol. The solution contained 3Å molecular sieves. The reaction mixture is stored at −30° C. The methanol is removed on the rotovap. Fresh methanol (20 ml) is added folowed by a stream of ammonia gas. The resulting mixture is heated to reflux for three hours. The reaction mixture is filtered at room temperature. The mother liquor is condensed and the resulting residue is purified by reverse phase HPLC (0-50% ACN/H2O). The product is isolated as a white solid with a melting point of 91-95° C. MS C20H21ClN6O m/z: 397, 399. Anal. cald. for C20H21ClN6O.3C2HF3O2: C, 42.26; H, 3.27; N, 11.37. Found C, 42.20; H, 3.44; N, 11.36.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), morpholine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 311 (M+, 2), 132 (3), 131 (5), 101 (6), 100 (bp), 56 (6).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1.[Cl:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[C:37]3[N:36]=[CH:35][N:34]=[C:22](NCC4(C5C=CC=CC=5)CC4)[C:21]=3[N:20]=[CH:19]2)[C@H:15]([OH:38])[C@@H:14]1[OH:39].C(N(CC)CC)C>C(O)=O>[Cl:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[C:37]3[N:36]=[CH:35][N:34]=[C:22]([NH:10][CH2:9][C:6]4([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[CH2:8][CH2:7]4)[C:21]=3[N:20]=[CH:19]2)[C@H:15]([OH:38])[C@@H:14]1[OH:39]
Reactant: NCC1(c2cccs2)CC1
Reactant: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(NCC3(c4ccccc4)CC3)ncnc21
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(NCC3(c4cccs4)CC3)ncnc21
Yield: 29 %

Procedure:
(1-Thien-2-ylcyclopropyl)methylamine (0.55 g, 3.6 mmol), see Example 3, 6-chloropurine-5'-deoxy-5'-chlororiboside-2',3'-isopropylidene (1.25 g, 3.6 mmol, as prepared in Example 5) and triethylamine (0.75 g, 7.5 mmol) are reacted together as described in Example 5. Aqueous formic acid hydrolysis gives 5'-chloro-5'-deoxy-N6-((1-thien-2-ylcyclopropyl)methyl)adenosine (0.44 g, 29%) as a light khaki solid foam m.p. 69°-75° C. Found: C, 50.53; H, 4.90; N, 15.90; Cl, 9.13; S, 7.22%. C18H20ClN5O3S calculated requires: C, 51.25; H, 4.74; N, 16.61; Cl, 8.42; S, 7.59%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4](=[CH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:5]#[N:6].[BH4-].[Na+]>C(O)C>[CH3:15][O:14][CH:3]([O:2][CH3:1])[CH:4]([C:5]#[N:6])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(OC)C(C#N)=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(OC)C(C#N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 2-dimethoxymethyl-3-(3-pyridyl)acrylonitrile, obtained according to the process of Example 4 (20.4 6, 0.1 mol), absolute ethanol (200 mL) and sodium borohydride (1.6 g, 0.042 mol) was stirred at room temperature overnight. Most of the ethanol was evaporated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated, washed with saturated brine, dried (Na2SO4) and evaporated in vacuo. The residual oil was distilled in vacuo to give a pale-yellow oil (19.1 g, 93%), bp. 130-140° C. (0.2 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (443 mg, 0.862 mmol) in CH2Cl2 (7 mL) at rt was added TFA (1.0 mL, 13 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with CH2Cl2 (10 mL), washed with aq. NaOH (1 N, 15 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (357 mg, 0.863 mmol, 100% yield) as a yellow solid. LCMS (m/z)=414 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16]OS(C)(=O)=O)[C@@H:13]([OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:16][C@@H:14]1[C@@H:13]([OH:22])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (125 mg) was then dissolved in N,N-dimethylformamide (3 mL) and sodium azide (50.0 mg) was added. The mixture was stirred at 100° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (5 mL). The solution was then washed with water (2×1 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: ethyl acetate) to give (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (91.0 mg). This compound was identical to the compound obtained by Process A.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44](Br)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][O:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].O1CCOCC1.Cl>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 18.1 %

Procedure:
A mixture of (S)-4-(1-benzyl-2-trityloxy-ethylamino)-3-[6-bromo-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one (150 mg, 0.216 mmol), morpholine (28.2 mg, 0.324 mmol), palladium acetate (2.4 mg, 0.01 mmol), tri-tert-buylphosphine (4.4 mg, 0.02 mmol), and sodium tert-butoxide (104 mg, 1.08 mmol) in toluene (5 mL) was heated to 100° C. for 14 h under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers were washed with water, brine, dried over Na2SO4. Concentration gave a brownish residue, which was treated with 4 N HCl dioxane solution (3 mL) at room temperature for 6 h. After removal of the solvent, the residue was purified by prep. HPLC to yield the title compound (18 mg, 18%). 1H NMR (400 MHz, CD3OD) δ 7.59 (1H, s), 7.12–7.28 (7H, m), 6.12 (1H, d, J=7.6 Hz), 4.01–4.08 (5H, m), 3.76 (1H, dd, J=4.8, 11.1 Hz), 3.71 (1H, dd, J=5.2, 11.1 Hz), 3.32–3.10 (4H, m), 3.09 (1H, dd, J=5.6, 13.7 Hz), 2.92 (1H, dd, J=8.0, 13.7 Hz), 2.65 (3H, s). LCMS (M+H)+ m/z 460 (t=1.30 min.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](B(O)O)([CH3:11])=[CH2:10].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]([CH3:11])=[CH2:10])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C=C(C)B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C=C(C)c1cccc(Br)n1
Temperature: 100 °C

Procedure:
In a tube were placed 2,6-dibromopyridine (100 mg, 0.422 mmol), isopropenylboronic acid (40 mg, 0.464 mmol), DME (1.5 mL), EtOH (500 μL), and 1M aqueous Na2CO3 (1 mL, 1.0 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (37 mg, 0.032 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 100° C. for 1 hour. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5% EtOAc/hexanes) afforded 2-bromo-6-isopropenylpyridine. Rf=0.45 (15% EtOAc/hexanes). LCMS=200.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.49 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 5.93 (s, 1H), 5.32 (m, 1H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.70 g) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.085 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.71 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (0.52 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[C:24]([CH:28]([CH:35]2[CH2:37][CH2:36]2)[NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:25]=[N:26][CH:27]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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]>[CH:35]1([CH:28]([C:24]2[CH:25]=[N:26][CH:27]=[C:22]([C:8]3[CH:9]=[CH:10][C:5]4[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=4[CH:7]=3)[CH:23]=2)[NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:37][CH2:36]1
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc3oc(=O)n(C)c3c2)c1)C1CC1
Yield: 53.5 %

Procedure:
The mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (115 mg, 0.42 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethane-sulfonamide (133 mg, 0.42 mmol), PdCl2(dppf).CH2Cl2 (34 mg, 0.04 mmol) and Na2CO3 (2 M in water, 0.42 mL, 0.83 mmol) in DMF (6 mL) was heated at 100° C. for 3 h. After concentration, the residue was diluted with DCM, and subsequently filtered to remove insoluble solid. The filtrate was concentrated and purified by flash column (MeOH—CH2Cl2, v/v, 0-4%) to give N-(cyclopropyl(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide (87 mg, 54%); ESI-MS m/z: 388 [M+1]+, Retention time 1.35 min; 1H-NMR (MeOD, 400 MHz) δ 8.80 (1H, d, J=2.0 Hz), 8.62 (1H, d, J=2.0 Hz), 8.20 (1H, t, J=2.0 Hz), 7.54 (1H, d, J=2.4 Hz), 7.50 (1H, dd, J=8.4, 24 Hz), 7.42 (1H, d, J=84 Hz), 3.95 (1H, d, J=8.8 Hz), 3.52 (3H, s), 3.05-2.92 (2H, m), 1.36-1.30 (1H, m), 1.30 (1H, t, J=7.2 Hz), 0.81-0.77 (1H, m), 0.66-0.62 (2H, m), 0.55-0.47 (1H, m)