Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([C:24]([F:27])([F:26])[F:25])[O:13][CH:11]([OH:12])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:12][CH:11]1[O:13][C@@H:14]([C:24]([F:27])([F:26])[F:25])[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: OC1C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C(F)(F)F)O1
Product: CC(=O)OC1C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](C(F)(F)F)O1

Procedure:
Step (9'): The 1-hydroxyl group of Compound 74 is then acetylated with acetic anhydride to produce 1-O-acetyl-3,4-di-O-benzyl-2,6-dideoxy-6,6,6-trifluoro-L-lyxo-hexopyranose [Compound 75] of the formula ##STR115##
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([CH3:33])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26](OCC)=[O:27])=[N:24][C:20]=3[CH:19]=2)[CH2:14]1.[NH2:34][C:35]1[C:36]([C:41]#[N:42])=[N:37][CH:38]=[CH:39][CH:40]=1>C1COCC1>[NH2:42][C:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][N:37]=2)[NH:34][C:26](=[O:27])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:16][CH2:17][CH:13]([N:12]([CH3:11])[CH3:33])[CH2:14]3)=[CH:19][C:20]=2[N:24]=1
Reactant: N#Cc1ncccc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCC(N(C)C)C3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3[nH]c(-c4c(N)c5ncccc5[nH]c4=O)nc3c2)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl {5-[3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}acetate (1.0 eq) and 3-aminopyridine-2-carbonitrile (J. Org. Chem. 1958, 1616-1617; 1.0 eq) in THF at 0° C. The reaction was stirred overnight and then heated at 40° C. for 3 hours. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 390.2 (MH+), Rt 1.79 minutes.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 59.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azetidin-1-yl-2-chloroethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.8 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH2:34][N+:35]#[C-:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1.[C-]#N.[Na+]>CCO>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]4[O:23][CH:36]=[N:35][CH:34]4[S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=4)(=[O:33])=[O:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)C2N=COC2C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.6 mmol) and TosMIC (340 mg, 1.7 mmol) were dissolved in EtOH (20 ml), to which NaCN (12 mg, 0.25 mmol) was added. The solution immediately turned pale yellow and was allowed to stir for 2 hours at room temperature. The solvent was removed in vacuo and the residue was taken up in DCM (10 ml) and washed with saturated sodium bicarbonate solution (15 ml), followed by brine (15 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazole as a pale brown foam (500 mg). LRMS ESI+ m/z 513 [MH]+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.I[CH2:40][CH3:41].[H-].[Na+].O>CN(C)C=O>[N:4]1([C:7]2[C:12]([N:13]([CH2:40][CH3:41])[C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:25])=[CH:21][C:22]=4[F:24])[N:17]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:15]=3[CH3:32])=[CH:11][C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCI
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1cc(N2CCOCC2)cnc1N1CCOCC1)c1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 60 °C
Reaction time: 41 h

Procedure:
To a stirred solution of N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.050 g, 0.096 mmol), in N,N-dimethylformamide (1.0 mL) was added iodoethane (0.030 g, 0.193 mmol) followed by 60% sodium hydride (7.71 mg, 0.193 mmol). The reaction was heated to 60° C. and stirring continued for 41 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0-50% EtOAc/hexane) to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-N-ethyl-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (1H, d, J=4.3 Hz), 8.02 (1H, s), 7.83-7.90 (1H, m), 7.77-7.83 (1H, m), 7.61-7.69 (2H, m), 7.35 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 6.86-7.00 (2H, m), 3.77-3.98 (6H, m), 3.21 (4H, br. s.), 2.95 (4H, s), 2.88 (3H, s), 2.48 (4H, br. s.), 2.12 (3H, s). Mass Spectrum (ESI) m/e=547.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]2)=[N:14][CH:13]=1)([O-:17])=[O:16]
Reactant: OC1CCCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(N2CCCC(O)C2)nc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
To a stirring solution of piperidin-3-ol (0.333 g, 3.29 mmol) and 2-chloro-5-nitropyrimidine (0.500 g, 3.13 mmol) in DMF (8 mL) was added K2CO3 (1.04 g, 7.52 mmol). The resulting yellowish suspension was stirred at 70° C. for 1.5 h. After this time, the reaction was determined to be complete by LC/MS. The reaction mixture was cooled to rt, then partitioned between water and EtOAc. The separated aqueous phase was extracted with EtOAc (2×). The combined EtOAc extracts were washed with water (1×), saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The resulting residue was dried under vacuum for 30 min to afford the desired product 1-(5-nitropyrimidin-2-yl)piperidin-3-ol (536 mg, 2.391 mmol, 76% yield) as a yellow solid. Anal. Calcd. for C9H12N4O3 m/z 224.2, found: 225.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 9.17-8.91 (m, 2 H), 4.20 (dd, J=13.14, 3.03 Hz, 1 H), 4.03 (ddd, J=13.07, 7.14, 3.79 Hz, 1 H), 3.96-3.74 (m, 2 H), 2.95 (s, 1 H), 2.11-1.87 (m, 2 H), 1.81-1.50 (m, 3 H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]=[C:10]1[N:11]=[C:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][C:14](=[O:32])/[C:15]/1=[CH:16]/[C:17](/[C:20]([C:22]1[N:30]2[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]2)=[CH:24][C:23]=1[CH3:31])=[O:21])=[CH:18]\[CH3:19]>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:24]1[C:23]([CH3:31])=[C:22]([C:20](/[C:17](=[CH:18]/[CH3:19])/[CH:16]=[C:15]2\[C:10](=[CH2:9])[N:11]=[C:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:13][C:14]\2=[O:32])=[O:21])[N:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]2
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)c(Br)c2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
N-Bromosuccinimide (10.64 g; 59.8 mmol) is added portionwise to a solution of (5E)-4-methylidene-5-{(2E)-2-[(2-methylindolizin-3-yl)carbonyl]but-2-en-1-ylidene}-2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (22.8 g; 59.8 mmol) in 350 mL of DCM and 105 mL of NMP. After 10 min of stirring at ambient temperature, the yellow precipitate formed is filtered off, washed with DCM and dried under vacuum to give 23.2 g (85%) of the yellow powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: NCCCCO
Product: O=C(NCCCCO)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
1,3-Benzodioxole-5-carboxylic acid (2.0 g, 12.0 mmol) and 4-amino-1-butanol (1.4 ml, 15.6 mmol) were coupled according to the procedure of Example 17 to 2.1 g (75% yield) of a pale yellow solid. MP 95-98° C.; 1H NMR (DMSO-d6): δ 1.38-1.65 (m, CH2, CH2), 3.31 (q, CH2), 3.39 (q, CH2), 4.39 (t, NH), 6.08 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H), 7.4 (d-d, 1 Ar H), 8.27 (t, NH) Electrospray Mass Spec: m/z 238.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:31]([N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][CH3:29])=[O:32])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CCN(Cc1ccccc1)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.130 g, 0.34 mmol), N-ethyl-N-benzylcarbamoyl chloride (0.081 g, 0.41 mmol), 4-dimethylaminopyridine (0.010 g, 0.08 mmol), and triethylamine (0.12 mL, 0.85 mmol) were combined in CH2Cl2 (5 mL) and stirred at reflux overnight. The mixture was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][C:10]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]3[C:11]=2[N:12]=[C:13]([O:25]C)[C:14]([O:23]C)=[N:15]3)=[CH:5][CH:4]=1.Br>C(O)(=O)C.C(OCC)C>[Br-:1].[N+:20]([C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:25])[C:14](=[O:23])[NH:15]2)=[C:10]([CH2:9][N+:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:8][CH:7]=2)[CH:19]=1)([O-:22])=[O:21]
Reactant: COc1nc2cc([N+](=O)[O-])cc(C[n+]3ccc(N)cc3)c2nc1OC
Agent: Br
Agent: [Br-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1cc[n+](Cc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)cc1
Reaction time: 0.17 h

Procedure:
212 mg (0.5 mmol) of 4-amino-1-(2,3-dimethoxy-7-nitro-quinoxalin-5-yl methyl)-pyridinium bromide are stirred in 3 ml of a 48% solution of hydrogen bromide in glacial acetic acid for 18 hours at room temperature. The brownish reaction mixture is diluted with 7 ml of diethyl ether and then stirred for 10 minutes. The resulting solid is filtered off, washed with a small amount of diethyl ether and dried. The title compound is obtained in the form of a yellow solid having a melting point of>245° C. (decomp.).
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:14])=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:10]2[C:11]([CH3:14])=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2c(C)csc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2c(C)csc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Ethyl 4-(acetyloxy)-3-methyl-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (500 mL). Potassium carbonate (35 g, 0.25 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (2:1) to give the desired product 19.5 g (82 mmol, 60%) as a cream solid. 1H NMR (DMSO-D6): δ ppm 1.35 (t, 3H), 2.60 (s, 3H), 4.20 (qt, 2H), 7.29 (m, 1H), 7.35 (s, 1H), 7.95 (s, 1H); MS (APCI, pos): 237.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]=[C:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=2)[NH:20]1>>[OH:18][C:19]1[NH:20][C:21]2[C:26]([C:27]=1[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][N:7]=1)=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(S(=O)(=O)N4CCN(C)CC4)cn3)c2c1

Procedure:
The title compound was prepared as described for Example 103 using 1-[(6-chloropyridine-3-yl)sulfonyl]-4-methylpiperazine (described in: Thunus. L. Annales Pharmaceutiques Francaises 1977, 35, 197-204) and methyl 2-oxoindoline-5-carboxylate to give the title compound in 59% yield, but without the treatment of the base with hydrochloric acid to from the salt: 1H NMR (D2O, 400 MHz) δ 8.03 (d, J=2 Hz, 1H), 7.44 (m, 1H), 7.30 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.82 (d, J=9 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.93 (m, 2H), 3.82 (s, 3H), 3.65 (m, 2H), 3.28 (m, 2H), 3.03 (m, 2H), 2.94 (s, 3H); MS (TSP) m/z 431 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]2=[O:33])=[N:23][C:22]=1[CH3:34])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=3)=[CH:28][C:27]2=[O:33])=[N:23][C:22]=1[CH3:34])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1nc(CCl)cs1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3csc(C(C)C)n3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)-2-isopropylthiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 36% yield: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 7.34-7.23 (m, 5H), 7.21 (s, 1H), 6.28-6.20 (m, 1H), 6.10-6.04 (m, 2H), 5.12 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 3.38-3.27 (m, 1H), 2.68 (s, 3H), 1.45-1.35 (m, 6H); MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 25.4 g of 2amino-4-methyl-6-methoxypyrimidine in 150 ml concentrated hydrochloric acid was cooled to ca. 0° C. and treated with a solution of 25.3 g of sodium nitrite in 50 ml water, added over a period of 30-40 minutes. The thick orange reaction mixture was stirred at room temperature for 4-5 hours and then adjusted to pH 10 by addition of 12.5N sodium hydroxide solution. The precipitate was filtered and extracted thoroughly with approximately 600 ml of hot ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 7.2 g of 2-chloro-4-methyl-6-methoxypyrimidine as a white, crystalline solid, m.p. 36°-38° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18]C(=O)OCC2C=CC=CC=2)[CH:12]=[N:13][CH:14]=1.B(Br)(Br)Br.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].[NH4+].[Cl-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1)OCc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a solution of benzyl 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropylcarbamate (94 mg, 0.227 mmol) in DCM (3 ml) was added BBr3 (0.682 ml, 0.682 mmol) at 0° C. This reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by addition of saturated NaHCO3 solution, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in pyridine (3.00 ml), and ethanesulfonyl chloride (0.086 ml, 0.910 mmol) was added to the solution. This reaction mixture was stirred at room temperature. After 1 h, saturated NH4Cl solution in water was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (EtOAc/Heptane=0-50%, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide (6.2 mg, 0.017 mmol, 7% yield). ESI-MS m/z: 371[M+1]+. 1H NMR (CDCl3, 400 MHz) 1.31 (t, J=7.2 Hz, 3H), 1.38-1.43 (m, 2H), 2.35-2.38 (m, 1H), 2.86-2.91 (m, 1H), 3.14 (q, J=7.2 Hz, 2H), 7.41 (dd, J=7.6, 2.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.57 (t, J=2.0 Hz, 1H), 7.65 (dd, J=7.6, 2.0 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])(C)[CH3:2].C([Mg]Cl)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35](NOC)=[O:36])[C:30]=1C>C1COCC1>[C:4]([SiH:1]([CH3:2])[O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15]([C:35]([C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[CH:33][N:32]=2)=[O:36])=[CH:14]1)([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Reactant: CONC(=O)c1nccc(Cl)c1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[SiH](OCC(C)(C)n1cc(C(=O)c2cc(Cl)ccn2)c2cnccc21)C(C)(C)C
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 60.8 %

Procedure:
1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 65, 3.99 g, 9.06 mmol) was dissolved in THF (75 mL) and the solution was degassed and cooled to −5° C. 2M iPrMgCl in THF (5.44 mL, 10.9 mmol) was added dropwise and the resulting yellow solution stirred at this temperature for 45 minutes. A solution of 4-chloro-N-methoxy-M-methylpicolinamide (2.18 g, 10.9 mmol) in THF (20 mL) was added dropwise and the reaction allowed to warm to room temperature for 4.5 hours. The reaction was partitioned between saturated aqueous ammonium chloride solution (30 mL) and EtOAc (50 mL), the organic layer was collected, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-90% EtOAc in DCM to afford the title compound as an orange oil (2.37 g, 59%). Taken on to the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[C:34](C1C=CC(F)=C([C@]23CO[C@@H](C4ON=C(C)C=4)C[C@H]2CSC(NC(=O)C2C=CC=CC=2)=N3)C=1)#[N:35]>>[C:34]([C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:17][O:16][C@@H:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:9]3)[CH:7]=1)#[N:35]
Reactant: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Product: Cn1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)cn1

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Bromo-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C46) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C37) as in Example 10. The product was obtained as a white solid. Yield: 265 mg, 98%. LCMS m/z 476.2 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.11 (br d, J=7.4 Hz, 2H), 7.98 (br s, 1H), 7.83-7.85 (m, 1H), 7.64-7.67 (m, 3H), 7.54-7.58 (m, 2H), 7.40-7.53 (m, 1H), 4.77 (dd, J=11.4, 2.2 Hz, 1H), 4.25-4.29 (m, 1H), 4.07-4.12 (m, 1H), 3.96 (d, J=11.5 Hz, 1H), 3.84 (s, 3H), 2.93-2.97 (m, 1H), 2.80 (dd, J=13.2, 2.6 Hz, 1H), 2.13-2.120 (m, 1H), 1.97-2.01 (m, 1H).