Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[SH:5][CH:6]([CH2:14][CH2:15][SH:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:16][CH2:15][CH2:14][CH:6]([SH:5])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(O)CCCCC(S)CCS
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(S)CCCCC(=O)O
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
Acetyl chloride (0.30 g, 3.8 mmol) in 4 mL of dry methylene chloride was added dropwise under a nitrogen atmosphere over 10 min to a stirred solution of 6,8-bismercaptooctanoic acid (0.80 g, 3.8 mmol) and triethylamine (1.16 g, 11.5 mmol) at 0. The solution was stirred at 0 a further 15 min then at room temperature for 2 hr. The solution was diluted to 75 mL with methylene chloride and extracted with 2×50 mL of 10% aqueous citric acid, then washed with 30 mL of saturated brine. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The oil remaining was dissolved in 8 mL of 2-propanol and 8 mL of water added. The mixture was stirred under nitrogen at 40 for 4.5 hr. The solvent was evaporated in vacuo and the crude product mixture separated by column chromatography on silica gel first using ethyl acetate—hexane—acetic acid (100:100:1, v/v) as the eluting solvent, and then rechromatographed using hexane-ethyl acetate-acetic acid (150:100:1, v/v) as the solvent yielding 51 mg (5%) of pure 8-acetylmercapto-6-mercaptooctanoic acid as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1B(O)O.C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2cncc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)c2)c1

Procedure:
By following a procedure analogous to Example 122 starting from 2-fluoro-5-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2-fluoro-5-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=48%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:3].[C:11](Cl)(=[O:13])[CH3:12]>C1COCC1>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C@@H:2]([NH:1][C:11](=[O:13])[CH3:12])[CH3:3])=[N:9][CH:8]=1
Reactant: C[C@H](N)c1ccc(O)cn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(O)cn1
Reaction time: 2 h

Procedure:
To 1.00 g (5.73 mmol) (S)-6-(1-aminoethyl)pyridin-3-ol in 10 ml THF and 3.99 mL TEA (28.6 mmol) are slowly added 494 mg (6.30 mmol) acetyl chloride and stirring is continued for 2 h. The reaction is quenched by the addition of water and extracted several times with DCM. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH/NH3 90/9/1).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[O:25])[C:6]1=[O:29]
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCC(C)(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethyl-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.29 (1H, t, J=6 Hz), 8.51 (1H, s), 7.72 (1H, s), 7.31 (2H, dd, J=9, 5.6 Hz), 7.12 (2H, t, J=9 Hz), 5.13 (2H, s), 4.76 (1H, t, J=5 Hz), 4.11 (2H, s), 3.25 (2H, d, J=6 Hz), 3.17 (2H, d, J=5 Hz), 3.12 (3H, s), 2.82 (3H, s), 0.83 (6H, s); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2188.
Reaction SMILES: Cl[Si](C)(C)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].Cl>ClCCl>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13]([NH:6][C:11]1[CH:10]=[CH:9][C:8]2[CH2:25][CH2:24][CH2:23][CH2:22][C:7]=2[C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:19]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 418A (1.81 g, 8.35 mmol) in dichloromethane (25.5 mL) was treated with chlorotrimethylsilane (6.7 mL of 1M CH2Cl2 solution, 16.7 mmol) and pyridine (25.5 mL), stirred at room temperature for 10 minutes, treated with methyl 2-(chlorosulfonyl)benzoate (2.61 g, 11.11 mmol), stirred overnight at room temperature, and treated with 1N HCl (50 mL). The aqueous phase was extracted with dichloromethane two times and the combined organic phases were washed with water and brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 404 (M+H)+; 480 (M+Na)+; (ESI(−)) m/e 402 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.77-7.65 (m, 4H), 7.12 (d, 1H), 6.98 (d, 1H), 3.01 (s, 3H), 3.63 (s, 3H), 2.68 (br s, 2H), 2.53 (br s, 2H), 1.66 (br m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C(=O)OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonylindole-6-carboxylate (1.27 g) in 5.0% formic acid-methanol (20.0 ml) was added 10% palladium on carbon (1.27 g) and the mixture was stirred under nitrogen atmosphere at ambient temperature for 4 hours and stand overnight. The resulting solution was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the solution was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether:n-hexane (1:5) to give 1-tert-butoxycarbonylindoline-6-carboxylic acid (761 mg).
Reaction SMILES: [F:1][C:2]([F:30])([C:26]([F:29])([F:28])[F:27])[C:3]([F:25])([F:24])[C:4]([F:23])([F:22])[O:5][C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[O:8][C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:31]([O:36][C:37]1[CH:38]=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[N:41][CH:42]=1)[CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:31]([O:36][C:37]1[CH:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:19])([F:18])[C:6]([F:21])([F:20])[O:5][C:4]([F:23])([F:22])[C:3]([F:25])([F:24])[C:2]([F:30])([F:1])[C:26]([F:29])([F:28])[F:27])([F:17])[F:16])=[CH:47][CH:48]=2)=[N:39][CH:38]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCOc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride (5.17 g of 95% purity, 8.4 mmol) with 5-pentoxy-2-(4-hydroxyphenyl)pyrimidine (2.17 g, 8.4 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation to provide a yield of 3.6 g.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:9]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=[CH:6][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=CCC1
Temperature: 0 °C

Procedure:
A solution of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (312 g, 1.12 mol) and DBU (400 g, 2.24 mol) in THF (4.5 L) was heated to reflux overnight. The mixture was poured into ice-water (2 L) and then extracted with EtOAc (2 L). The combined organic phase was washed with 1 M HCl solution (4 L×2), aq. NaHCO3 (4 L), and dried over anhydrous sodium sulfate. The residue was concentrated to afford tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[N:30]1([C:36]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH:41]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(N2CCNCC2)c1
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+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (106.5 mg, 0.214 mmol), 2-(1-piperazinyl)-pyridine-4-boronic acid, pinacol ester (93 mg, 0.322 mmol), Pd(PPh3)4 (25 mg, 0.02147 mmol) and 2M potassium carbonate (0.321 mL, 0.642 mmol) in anhydrous dioxane (1.0 mL) was sparged with nitrogen for 5 minutes, then heated in microwave for 1 h at 100° C. Reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered, concentrated and used in next step without further purification. LCMS-ESI+: calc'd for C36H36ClN4O3S: 579.2 (M+H+); Found: 579.1 (M+H+).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:29]2[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38](OC)=[O:39])=[CH:31][C:30]=2[CH3:42])=[C:10]2[C:14]=1[C@H:13]([O:15][C:16]1[CH:28]=[CH:27][C:19]3[C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][O:22][C:18]=3[CH:17]=1)[CH2:12][CH2:11]2>O1CCCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:29]2[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38]3([OH:39])[CH2:2][CH2:1]3)=[CH:31][C:30]=2[CH3:42])=[C:10]2[C:14]=1[C@H:13]([O:15][C:16]1[CH:28]=[CH:27][C:19]3[C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][O:22][C:18]=3[CH:17]=1)[CH2:12][CH2:11]2
Reactant: CC[Mg]Cl
Reactant: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cc1cc(OCC2(O)CC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium chloride (380 μL of a 1 M solution in tetrahydrofurane) is added dropwise under argon to a solution of 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid in tetrahydrofurane (4 mL). The mixture is stirred at room temperature for 30 minutes. Ti(OiPr)4 (120 μL) is added dropwise and after stirring for 30 minutes ethylmagnesium chloride (1.15 mL of a 1 M solution in tetrahydrofurane) is added dropwise. The mixture is stirred for 2 hours, partitioned between ethylacetate and saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes. After filtering over celite the phases are separated, the aqueous phase is extracted with diethylether and the combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated and the residue is purified by HPLC on reversed phase. Yield: 38 mg; LC (method 8): tR=0.38 min; Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31]>CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:36]([C:35]3[CH:37]=[CH:38][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Yield: 30.6 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (1.0 molar, 0.7 ml) and 4-ethylaniline (0.093 g) to give the desired 8-(2-chloro-benzenesulfonyl)-2-(4-ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.068 g) as a light-brown solid. MS (ESI): 433.136 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:30])[C:25]2([CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[CH2:28][CH2:29][C:25]4([C:23]([F:30])([F:22])[CH2:24]4)[CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: FC1(F)CC12CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(C1)CC2(F)F

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1,1-difluoro-5-azaspiro[2.4]heptane hydrochloride (1215071-12-7) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=400.5 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Li+]>CO.O>[CH3:14][O:13][CH2:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:6][CH:7]=1
Reactant: COCSc1ccc(CC(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCSc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
A solution of (4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (441 mg, 1.90 mmol) in methanol (1 mL), water (0.5 mL), and tetrahydrofuran (0.5 mL) was treated with lithium hydroxide (51 mg, 2.1 mmol). The reaction mixture was stirred at 25° C. for 20 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water and extracted with ethyl acetate. The aqueous layer was then acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford (4-methoxymethylsulfanyl-phenyl)-acetic acid (402 mg, 100%) as a clear oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[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]([NH:26][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1nc(NC(=O)c2ccccc2F)sc1C(=O)NCc1ccccc1
Yield: 99 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-fluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 99% yield; 1H NMR (CDCl3, 300 MHz) δ 8.63 (t, J=5.8 Hz, 1H), 7.62-7.17 (m, 9H), 6.01 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 369.7 (M+1).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:25](OC)=[O:26])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:25][OH:26])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Lithium borohydride (2.12 g, 97.4 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (10.0 g, 24.3 mmol) in tetrahydrofuran (80 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C., and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the solid, which was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (8.31 g, 21.7 mmol, 89%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([OH:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].C([O-])([O-])=O.[K+].[K+].CS(C)=O.[CH2:32](I)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>Cl.CCOCC.CCCCCC.O.C(Cl)Cl>[CH3:21][N:2]([CH3:1])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([O:14][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: CCOC(=O)C(C(=O)N(C)C)=C(O)c1ccc(Cl)cc1Cl
Reactant: ICc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)N(C)C)=C(OCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A well stirred slurry of 10.0 g of N,N-dimethylalphaethoxycarbonyl-beta-hydroxy-2,4-dichlorocinnamamide, 8.3 g of powdered anh. K2CO3, and 100 ml of dry DMSO was heated to 100° C. for 30 min. To this mixture was added 6.5 g of benzyl iodide all at once and the mixture heated at 120° C. for 1 hour. The reaction was cooled to RT, 100 ml of CH2Cl2 and 100 ml of water added plus a few drops of concentrated HCl. The organic phase was collected, washed with saturated brine, dried with MgSO4, filtered and concentrated under reduced pressure to yield a light yellow gum. The crude product was taken up in a minimum amount of ether/hexane and the product allowed to crystallize, yielding 4.0 g of white solid, MP 115° C.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:33][O:34][C:35]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12>C1COCC1>[CH3:33][O:34][C:35]1[C:40]([CH:41]=[CH2:2])=[CH:39][N:38]=[C:37]2[N:43]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:44]=[CH:45][C:36]=12
Reactant: COc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1cnc2c(ccn2COCC[Si](C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a solution methyltriphenylphosphonium iodide (782 mg, 1.93 mmol) in dried THF (5 mL) was added 2.5 M n-BuLi in Hexane (0.74 mL, 1.85 mmol) at −78° C. After 10 minutes, 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (493 mg, 1.61 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature spontaneously. After 2 hours, the reaction mixture was quenched with water and was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 15% Ethyl acetate/Hexane) as a solvent to afford title compound (371 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.07 (dd, J=11.4, 18 Hz, 1H), 6.78 (d, J=3.6 Hz, 1H), 5.78 (d, J=18 Hz, 1H), 5.70 (s, 2H), 5.30 (d, J=11.4 Hz, 1H), 4.38 (s, 3H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 305 [M+1].
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:25])[NH:9][C:10]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.Cl[C:32]1N=C(C2C=CN=CC=2)C(C2C=CC(F)=CC=2)=CN=1.ClC1C(C2C=CC=CC=2)=C(C2C=CN=CC=2)N=C(C2C=CN=CC=2)N=1.C[O-].[Na+]>CO>[CH3:32][O:25][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:9]=1
Reactant: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1
Reactant: O=c1[nH]c(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1
Agent: C[O-]
Agent: Clc1nc(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1nc(-c2ccncc2)nc(-c2ccncc2)c1-c1ccccc1

Procedure:
A mixture of 5-phenyl-2,6-bis-(4-pyridyl)-4(3H)-pyrimidinone (360 mg, 1.10 mmol) and phosphorus oxychloride (2 ml) was heated at reflux for 1.5 h. Work-up was done as described for the preparation of 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine. To a solution of the crude 4-chloro-5-phenyl-2,6-bis-(4-pyridyl)-pyrimidine (250 mg, 0.73 mmol) in methanol (5 ml) was added methanolic 0.5 N sodium methoxide (1.45 ml, 0.73 mmol) and it was heated at reflux for 1 h. After evaporation, the resultant material was partitioned between ethyl acetate and water. The organic solution was washed with water, dried and evaporated. Chromatography of the crude product on a column of silica gel (ethyl acetate) provided the title compound. MS (m/z): 341.2 (M+H)+; C21H16N4O requir. 340.4 1H-NMR (CDCl3) 8.82, 8.54, 8.40 (3m, each 2H, Pyrid.), 7.40-7.18, (m, 7H, Ph. Pyrid.), 4.15 (s, 3H, CH3O).