Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
N-(tert-Butoxycarbonyl)-p-phenylenediamine (0.209 g, 1.002 mmol), triethylamine (0.101 g, 1.002 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.279 g, 1.002 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ethanol to obtain the titled compound (0.180 g, 0.319 mmol, 48%).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([C:11]([NH2:13])=[O:12])=[C:6]([S:4][CH:2]([CH3:3])[CH3:1])[C:7]=2[CH:17]=1
Reactant: CC(C)S
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SC(C)C)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
2-Propanethiol (1.1 mL, 12.4 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (3.00 g, 12.4 mmol) in 24 mL of DMF. Diazabicycloundecene (DBU) (1.8 mL, 12.4 mmol) is added and the mixture is warmed to 80° C. After 6 hours, additional amounts of 2-propanethiol (110 μL) and of DBU (180 μL) are added. Heating is continued for 1 hour. The reaction mixture is allowed to cool and then is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxamide in 80% yield. An analytical sample is obtained by a second recrystallization from ethyl acetate:hexane; mp=143°-143.5° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CC(N(C)C)=O>[Br:8][C:9]1[C:17]2[C:16]([N:40]3[CH2:41][CH2:42][C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:39]3)=[N:15][CH:14]=[N:13][C:12]=2[N:11]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Triethylamine (3.55 mL, 25.45 mmol) was added to 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 61) (3.28 g, 8.48 mmol) and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (WO2008075109) (3.07 g, 11.88 mmol) in DMA (50 mL) at 20° C. The resulting suspension was stirred at 70° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (200 mL), and washed sequentially with water (75 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylate (3.60 g, 69.7%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].BrCCF.[F:32][CH:33]([F:36])[CH2:34]I>>[F:32][CH:33]([F:36])[CH2:34][N:25]1[CH2:24][CH2:23][CH:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[N:21]=2)[CH2:27][CH2:26]1
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Reactant: FC(F)CI
Agent: FCCBr
Product: O=C(Nc1cccc(C2CCN(CC(F)F)CC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 32, substituting 1-(6-(piperidin-4-yl)quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea by 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) and 1-bromo-2-fluoroethane by 1,1-difluoro-2-iodoethane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N1C(C)=CC(C)=CC=1C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C=O)cc1O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=O)cc1OC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture containing 108 g. (710 mmol.) of 3-hydroxy-4-methoxybenzaldehyde, 500 ml. of chloroform, and 125 ml. of collidine was kept below 10° C., treated dropwise with 70 ml. (800 mmol.) of chloroacetyl chloride over a 1-hour period, and then stirred 2 hours at 25° C. The solution was serially extracted with 500-ml. portions of water, 0.3N HCl, and water (2×). Chloroform was evaporated and crude 3-chloroacetoxy-4-methoxybenzaldehyde was recrystallized from diethyl ether (147 g., 91%), m.p. 88°-89° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15]>CN(C=O)C.[Cu-]=O>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccccc1I
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: COC(=O)C#Cc1ccccc1OC
Temperature: 110 °C
Yield: 49.2 %

Procedure:
To a suspension of methyl propiolate (2, 1.314 ml, 15.41 mmol) and copper(I) oxide (1.086 g, 7.59 mmol) in DMF (20 ml) was added 1-iodo-2-methoxybenzene (1, 1.262 ml, 9.48 mmol). The resulting mixture was heated in a Microwave reactor to 110° C. for 2 hrs. The reaction mixture was filtered through a short pad of silica gel and washed w/EtOAc. The organic layer was washed w/1M HCl, brine and sat'd NaHCO3, dried (Na2SO4) and concentrated to leave an oil as crude product, which was purified by flash chromatography (SiO2, EtOAc/Hexane, 1:2) to afford methyl 3-(2-methoxyphenyl)propiolate 3 (932 mg, 4.66 mmol, 49.1% yield). 1H-NMR (500 MHz, CDCl3), δ: 7.54 (1H, dd), 7.44 (1H, td), 6.98-6.92 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9](=[O:14])[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:36])[C:32]([F:33])([F:34])[F:35])=[CH:28][CH:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CC(Oc1ccc(Br)cc1)C(F)(F)F
Product: CC(Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1)C(F)(F)F

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and rac-1-bromo-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene (Intermediate 35) in analogy to Example 1a): MS (ISP): 458.2 (M+H)+.
Reaction SMILES: ClC1N=C(CI)C=C(N2CCOC[C@@H]2C)N=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Cl:22][C:23]1[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:30][CH2:29][C:27]1[CH:26]=[C:25]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:24]=[C:23]([Cl:22])[N:28]=1)(=[O:20])=[O:19]
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Reactant: CS(=O)(=O)Cl
Agent: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
2-Chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine can also be prepared by the dropwise addition of methanesulfonyl chloride (91 mL, 1169.52 mmol) to [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (190 g, 779.68 mmol) and triethylamine (163 mL, 1169.52 mmol) in DCM (2293 mL) at 0° C. under air. The resulting solution was allowed to warm up slowly to RT over a period of 4 hours. The reaction mixture was quenched with water, extracted with DCM and the organic layer dried over MgSO4, filtered and evaporated to afford [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methyl methanesulfonate as a yellow gum (251 g). Sodium iodide (234 g, 1560.07 mmol) was added to this material in acetone (3679 mL) and the resulting suspension stirred at RT for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM and washed three times with water then with a saturated aqueous solution of sodium thiosulphate. The organic layer was dried over MgSO4, filtered and evaporated to afford crude desired product (270 g). This was purified by chromatography to give an off white solid which was further triturated with ether to give the desired material which was identical to previous samples.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:36][N+:37]#[C-:38])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)=[CH:38][N:37]=[CH:36]1
Reactant: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cnco3)ccc2n1
Yield: 34.9 %

Procedure:
To a suspension of 200 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 8) in 10 mL of methanol are added 104 mg of potassium carbonate and 147 mg of para-toluenesulfonylmethylisonitrile (TOSMIC). The reaction mixture is refluxed for 2 hours and then evaporated to dryness under reduced pressure, taken up in 300 mL of dichloromethane and washed with water. The organic phase is dried and concentrated to dryness on silica and then chromatographed on a silica cartridge, eluting with a gradient of from 0 to 20% of methanol in dichloromethane. The fractions containing the expected product are concentrated to dryness and the solid obtained is triturated with a small amount of dichloromethane, filtered off and dried to give 80 mg of 6-(oxazol-5-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[CH2:11])[CH:5]=[C:4]([CH:12](O)[CH3:13])[N:3]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[CH2:11])[CH:5]=[C:4]([CH:12]([Cl:17])[CH3:13])[N:3]=1
Reactant: C=Cc1cc(C(C)O)nc(Cl)c1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=Cc1cc(C(C)Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of 2-chloro-3-methoxy-4-vinyl-6-(1-hydroxyethyl)-pyridine (446 mg, 2.09 mmol) in 10 mL of methylene chloride at 0° C. is treated with thionyl chloride (0.227 mL, 3.13 mmol) and stirred at room temperature for 1 h. The reaction is quenched with 15 mL of saturated sodium bicarbonate. The aqueous layer is extracted with 3×10 mL of methylene chloride. The combined organics are dried over potassium carbonate and concentrated in vacuo to provide 447 mg (92%) of 2-chloro-3-methoxy-4-vinyl-6-(1-chloroethyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=CC=2N=N1.CN(C=O)C.C1(CN)CC1>C1COCC1>[CH:37]1([CH2:36][NH:32][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:25])[CH2:39][CH2:38]1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)NCC3CC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 22.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.406 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 1-cyclopropylmethanamine (0.044 g, 0.406 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 0.220 (q, J=4.5 Hz, 2H), 0.44 (q, J=6.6 Hz, 2H), 1.01 (m, 1H), 1.51 (s, 6H), 3.02 (s, 2H), 3.19 (t, J=6.0 Hz, 2H), 7.22 (s, 1H), 7.77 (s, 1H), 8.43 (s, 2H), 10.99 (s, 1H), 11.40 (s, 1H); MS [M+H]+: 446.27.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:9][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccccc1Oc1cccc(N)c1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1cccc(NCc2cccnc2)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-methoxyphenoxy)aniline (269 mg, 1.25 mmol) and pyridine-3-carboxaldehyde (107 mg, 1.00 mmol) was refluxed in methanol (2.5 mL) for 2 h, then cooled on an ice bath to 5° C. Sodium borohydride (95 mg, 2.5 mmol) was added and the mixture was warmed to room temperature, stirred for 2 h, concentrated in vacuo, and taken up in dichloromethane. The resultant suspension was filtered, the filtrate concentrated in vacuo, and the residue chromatographed on silica gel (eluted with 2% methanol/dichloromethane) to give N-(3-(2-methoxyphenoxy)phenyl)pyrid-3-ylmethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][CH2:19][C:20]([NH2:22])=[O:21].C([Al](CC)CC)C>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:18]([CH2:19][C:20]([NH2:22])=[O:21])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NCC(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CO
Product: NC(=O)Cn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 85 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2.5 g, 0.013 mol), methanol (50 mL, 1 mol), glycinamide hydrochloride (3.0 g, 0.027 mol) and triethylaluminum (4.4 mL, 0.033 mol) and heated at 85° C. for 3 hours. The solvent was removed under reduced pressure to get the product as a yellow solid. MS m/z=248.2 (M+H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][OH:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:53][C:54]1[C:59](O)=[CH:58][CH:57]=[CH:56][N:55]=1>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:59]3[C:54]([CH3:53])=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Reactant: Cc1ncccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was synthesised in essentially the same way as compound 18s. Compound 51 (Example 10; 80 mg, 0.30 mmol) and PPh3 (120 mg, 0.46 mmol) were dissolved in dry THF (1.5 ml). Then DIAD (90 μl, 0.46 mmol) and 2-methyl-3-hydroxypyridine (50 mg, 0.46 mmol) were added. The reaction mixture was stirred at RT for 48 hrs. After this time, the solvent was removed and the crude mixture purified by flash column chromatography (silica, DCM/MeOH 1:0 to 94:6) to afford compound 26s (75 mg, 71%). Analyses were performed on the free base. The compound was converted to the HCl salt for testing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[CH:6]=[CH:5]2.[CH:23]([Mg]Br)=[CH2:24]>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH:23]=[CH2:24])[CH:20]=[CH:21][CH:22]=1)[CH:6]=[CH:5]2
Reactant: C=C[Mg]Br
Reactant: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The aldehyde of Step 2 (35.93 g, 122 mmol) was suspended in 360 mL of toluene and cooled to 0° C. 1.0 M Vinylmagnesium bromide in THF (135 mL) was added into the addition funnel and the whole system was degassed by applying vacuum and flushed with nitrogen 3 times. The Grignard reagent was then added slowly at 0° C. and the mixture was stirred at 0° C. for 15 min. Cold 25% aq. NH4OAc was then added and the product was extracted in hot toluene, washed with brine, and dried over Na2SO4. The cloudy solution was filtered through celite, concentrated, and filtered through silica with EtOAc: toluene 10:90 to afford 32.04 g (81%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5](/[CH:6]=[CH:7]/N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1.C[O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)C(Cl)=O)=[O:20]>>[Cl:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:14][C:7]([C:28]1[CH:29]=[C:21]([CH:22]=[CH:23][CH:27]=1)[C:19]([OH:20])=[O:18])=[CH:6]2
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Product: O=C(O)c1cccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)c1

Procedure:
Starting from trans-4,5-dichloro-2-nitro-β-dimethylaminostyrene and 3-(methoxycarbonyl)benzoyl chloride and following successively the procedures of Descriptions 2, 3 and 4 afforded the title compound as a beige solid which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CCOC(C)=O>C(OC(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24][NH:30][CH2:29][CH2:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Reactant: NCCO
Solvent: CC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: O=C(CNCCO)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 55 °C

Procedure:
To a solution of the product from Step C (6.9165 g, 17.25 mmol) in 25 mL of isopropyl acetate was added ethanolamine (3.84 mL, 63.7 mmol). The reaction was warmed to 55° C. for 4 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C)C=O>[C:32]([S:34][CH:25]1[CH2:26][N:23]([C:20]2[S:21][CH:22]=[C:18]([C:16](=[O:17])[NH:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:11][CH:12]([CH3:13])[CH3:14])[N:19]=2)[CH2:24]1)(=[O:35])[CH3:33]
Reactant: CC([O-])=S
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (840 mg, 1.71 mmol) (obtained as described in Reference Example 37(5)) in dimethylformamide (42 ml) was added potassium thioacetate (1.17 mg, 10.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidine (452 mg, yield 56%) as a pale brown oil.