Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:36][C:6]1[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:29])[N:11]2[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of (S)-5-hydr oxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.063 mmol), β-alanine (672 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 535.39 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>>[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:32])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(N)c(C(F)(F)F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-amino-3-(trifluoromethyl)benzoic acid as starting compounds. The crude product is purified by column chromatography (silica gel and DCM/methanol=4:1) and crystallization from methanol to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19].O>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(F)cc1
Yield: 75.8 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.441 mole) of ethyl 2-chloro-(p-fluoro)-benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([N:20]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]1[C:26]([C:27]([O:29]CC)=O)=[C:25]([Cl:32])[N:24]=[C:23]([S:33][CH3:34])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH2:13]([N:20]1[C:21]2[N:22]=[C:23]([S:33][CH3:34])[N:24]=[C:25]([Cl:32])[C:26]=2[C:27](=[O:29])[CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a cooled solution at 0° C. of diisopropylamine (51.0 mL, 0.361 mol) in tetrahydrofuran (600 mL) was added n-BuLi (221 mL, 0.353 mol, 1.6 M in hexane) dropwise and the mixture was stirred at the 0° C. for 45 min. The reaction mixture was then cooled to −78° C. and a solution of ethyl 4-(benzyl(3-ethoxy-3-oxopropyl)amino)-6-chloro-2-(methylthio)pyrimidine-5-carboxylate (50 g, 0.114 mol) in tetrahydrofuran (500 mL) was added drop wise over 45 min. The reaction mixture was stirred at -78° C. for 15 min before water (1 L) was added. The reaction mixture was then warmed to room temperature and the organic phase was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with water (1 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude ethyl 8-benzyl-4-chloro-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate that was used for next step directly.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]#[C:12][CH2:13][CH3:14])(=O)OC.[CH:17]([C@H:19]1[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]2[C@@H:20]1[CH2:21][C:22](=[O:36])[O:23]2)=O>>[C:28]([O:27][C@@H:26]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][C:22](=[O:36])[O:23]2)[C@H:19]1/[CH:17]=[CH:7]/[C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][C:11]#[C:12][CH2:13][CH3:14])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCC#CCC(C)C(=O)CP(=O)(OC)OC
Product: CCC#CCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 90 %

Procedure:
Analogously to Example 1(g), 14.2 g of the title compound was synthesized from 9.85 g of 3-methyl-2-oxooct-5-inylphosphonic acid dimethyl ester and 11 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].
Reaction SMILES: I.[F:2][C:3]1[CH:4]=[C:5]([NH:16][C:17](SC)=[NH:18])[CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:57][NH2:58]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:58][N:57]=[C:17]([NH:16][C:5]2[CH:4]=[C:3]([F:2])[C:8]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[C:7]([F:15])[CH:6]=2)[N:18]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=1
Reactant: NN
Reactant: CSC(=N)Nc1cc(F)c(-n2cnc(C)n2)c(F)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)cc1
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2c(F)cc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)cc4)n3)cc2F)n1

Procedure:
Methyl 3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.942 g, 2.92 mmol, from preparation R) and 6-chloro-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (0.890 g, 2.86 mmol, from preparation AI) were coupled [N-methylmorpholine (0.1.26 mL, 11.0 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.360 mL, 11.5 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, crude 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown solid. The crude product was used in the next step without purification. LC-MS (M+H)+ 542.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:26][CH:21]([C:22](=[O:25])[CH:23]=4)[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:26][CH:21]([C:22](=[O:25])[C:23]=4[Cl:27])[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Temperature: 25 °C

Procedure:
A solution of 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (0.737 g, 2.17 mmol) in 15 mL of dimethylformamide was heated to 60° C. and N-chlorosuccinimide (0.290 g, 2.17 mmol) was added. After heating for 45 minutes, additional N -chlorosuccinimide (0.074 g, 0.55 mmol) was added. After heating for 55 minutes more, the reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel (elution with 15:85 to 80:20 EtOAc/hexanes) to yield 2-benzyl-6-chloro-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]([O-])=O.[Na+].[CH3:21][C:22]1[CH2:23][C:24](=[O:37])[N:25]([C:27]2[CH:36]=[CH:35][C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=2)[N:26]=1.C(=O)(O)[O-].[Na+]>Cl>[OH:16][C:3]1[C:2]([NH:1][N:17]=[C:23]2[C:24](=[O:37])[N:25]([C:27]3[CH:36]=[CH:35][C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=3)[N:26]=[C:22]2[CH3:21])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(-c2c[nH]c(C(=O)O)c2)c1O
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1=NNc1cccc(-c2c[nH]c(C(=O)O)c2)c1O
Yield: 27.7 %

Procedure:
4-(3-Amino-2-hydroxy-phenyl)-1H-pyrrole-2-carboxylic acid 57i (130 mg, 0.43 mmol) was dissolved in hydrochloric acid (1.5 mL, 1 mol/L) upon cooling by an ice-water bath, followed by dropwise addition of 0.6 mL of aqueous sodium nitrite (33 mg, 0.47 mmol). After the mixture was reacted for 10 minutes, 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 3i (89 mg, 0.3 mmol) was added. The mixture was adjusted to pH 8˜9 with saturated aqueous sodium bicarbonate. The reaction mixture was reacted at room temperature for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 15 mL of water. The mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid upon cooling by an ice-water bath. The mixture was filtered and the filter cake was washed with ethyl acetate and dried to obtain the title compound 4-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-1H-pyrrole-2-carboxylic acid 57 (38 mg, yield 21.3%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17]OC1=O>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][Cl:11])[C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1CCCl
Reactant: O=C=Nc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1c1cccc(Cl)c1
Temperature: 195 °C
Yield: 78.7 %

Procedure:
A mixture of 3-chlorophenyl isocyanate (7.65 g, 50 mmoles), N-(2-chloroethyl)-2-oxazolidinone (7.5 g, 50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give 10.2 g (78.4 percent) of the desired product, m.p. 64° C.
Reaction SMILES: C[O:2][C:3]1C=C(C=CC=1)C=C.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.N1CCCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:45]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[O:2]=[CH:3][C:17]1[CH:12]=[CH:13][C:14]([OH:45])=[C:15]([O:18][CH3:19])[CH:16]=1
Reactant: C=Cc1cccc(OC)c1
Reactant: O
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1cc(C=O)ccc1O
Yield: 50 %

Procedure:
The obtained 4-hydroxy, 3-methoxystyrene was taken in a 100 ml round bottom flask fitted with a condenser and mixed with para-iodo anisole (1.9 mmol), piperidine (4.5 mmol), palladium acetate (0.076 mmol), triphenylphosphine (0.089 mmol) and DMF (20 ml). The flask was shaken well and placed inside the monomode microwave oven and irradiated (250 W, 160° C.) for 30 minutes in parts. After completion, the reaction mixture was poured in ice cooled water and extracted with ethyl acetate. The organic layer was washed with dil. HCl, brine and water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel by column chromatography using a mixture of hexane and ethyl acetate (9:1 to 6:4) provided a white solid; 50% yield (20% overall yield starting from vanillin) (m.p. 163-166° C.); 1H NMR (CDCl3) δ 7.37 (2H, d), 6.95 (2H, d,), 6.84 (5H, m), 3.88 (3H, s), 3.76 (3H, s); 13C NMR (CDCl3) δ 159.0, 146.7, 145.3, 130.4, 127.4, 126.6, 126.1, 120.1, 114.5, 114.1, 108.0, 55.9 and 55.3.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH2:13])[CH:12]=1
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnn(C)c2Br)cn1N
Reaction time: 2.5 h

Procedure:
tert-Butyl [4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-yl]carbamate (5.00 g, 14.0 mmol) was dissolved in dichloromethane (120 mL), treated with trifluoroacetic acid (20.9 mL, 281 mmol), and stirred for 2.5 hours. After removal of volatiles in vacuo, the oily residue was diluted with diethyl ether (100 mL). The resulting suspension was stirred for 30 minutes at room temperature, and then the solid was collected and washed with diethyl ether to provide the product as an off-white solid. Yield: 4.98 g, 13.5 mmol, 96%. LCMS m/z 256.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 2.65 (s, 3H), 3.95 (s, 3H), 7.68 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[OH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2>N1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:8])=[CH:3][CH:2]=1
Reactant: CN(CCCO)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCCCN(C)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Yield: 97 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at −18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100% yield). p-Toluoyl chloride (4.26 g, 27.56 mmol) was added dropwise over 10 min to an ice-cooled solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (7.8 g, 25.05 mmol) in pyridine (100 ml). The resultant mixture NA as stirred for 2 h at 0° C., concentrated in vacuo and redissolved in ethyl acetate. The solution was washed with 10% citric acid and brine, then separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 30% ethyl acetate/hexane to give (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (97% yield). A solution of (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (0.91 g, 2.12 mmol) and triethylamine (5.0 ml) in DMF (5 ml) was stirred for 1 h at +80° C. The resultant mixture was cooled to room temperature and compound 1 (2.01 g, 1.74 mmol) was added. The reaction was diluted with DMF (5), stirred for 2 days, and then diluted with ether (100 ml). The precipitated solid was isolated by filtration, washed with ether and vacuum dried to afford compound 2b (89% yield) as a pale solid, which was sufficiently pure to be used in the next step without additional purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:17]=1)=[O:14]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure O and Scheme W using 3-phenyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 365.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([NH:8][CH3:9])=[N:6][N:7]=1.[C:10]([Cl:13])(Cl)=[O:11]>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:4][C:5]([N:8]([CH3:9])[C:10]([Cl:13])=[O:11])=[N:6][N:7]=1
Reactant: CNc1nnc(SC)s1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CSc1nnc(N(C)C(=O)Cl)s1

Procedure:
2-Methylthio-5-methylamino-1,3,4-thiadiazole (0.1 mole) and a solution of phosgene (0.11 mole) in benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of benzene and unreacted phosgene to yield the desired product N-(2-methylthio-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([O:23][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of Compound 224 (1.10 g, 3.60 mmol) in dry CH2Cl2 (10 mL) under ice-cooling was added successively 2,6-lutidine (0.59 mL, 5.07 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.99 mL, 4.31 mmol), the resultant homogeneous solution was then stirred at 25° C. for 30 minutes. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, ethyl ether-petroleum ether-benzene=1:2:2) to give Compound 225 (1.475 g, 98 percent): white solid; mp 123°-125° C.; Rf =0.50 (silica, 33 percent ethyl ether in benzene); IR (CHCl3) νmax 2952, 2933, 1621, 1506, 1336, 1295, 1256, 1240, 1174, 1151, 1090, 1025, 838 cm-1 ; 1H NMR (300 MHz, CDCl3) δ8.61 (s, 1 H, H6), 7.98 (d, J=9.2 Hz, 1 H, 1), 7.55-7.48 (m, 3 H, H4 and aromatic), 7.46-7.34 (m, 3 H, aromatic), 7.27 (dd, J=9.2, 2.7 Hz, 1 H, H2), 5.42 (t, J=2.6 Hz, 1 H, H10), 5.20 (s, 2 H, benzylic), 3.04-2.93 (m, 1 H, H7), 2.87-2.72 (m, 1 H, H7), 2.26-2.05 (m, 2 H, H8 or H9), 1.92-1.76 (m, 2 H, H8 or H9), 0.84 (s, 9 H, SiC(CH3)3), 0.22 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity) 420 (M+H, 100), 362 (23), 330 (3), 288 (9); HRMS for C26H34NO2Si (M+H), calcd 420.2359, found 420.2360.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.N1C=CC=CC=1.[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.C(OCC)(=O)C>[Br:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1)=[O:28]
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(N)n1
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)OC(C)(C)C)cc(NC(=O)CCCBr)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of t-butyl 2-amino-6-methoxypyridine-4-carboxylate (D55) (0.263 g) and pyridine (0.12 mL) in dichloromethane (16 mL) under argon, was added 4-bromobutyryl chloride (0.17 mL) dropwise (syringe). The reaction was stirred at room temp for 2.5 h and then diluted with ethyl acetate. The mixture was washed with citric acid solution (10% aq.) and the aqueous layer was re-extracted with ethyl acetate. The combined extracts were washed with aq. bicarbonate, water and brine, dried (MgSO4) and evaporated to give the title compound (D56) as a pale yellow gum (0.47 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (29) and N,N-diisopropylethylamine in dry dichloromethane was added. Water was added and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate. The purification gave N-benzyloxyacrylamide (30).