Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: ICC1CCC1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OCC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.4 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (200 mg) in DMF (5 mL) were added potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg), and the mixture was stirred at room temperature for 15 hr. Potassium carbonate (210 mg) and (iodomethyl)cyclobutane (150 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][CH:36]=1)[CH2:13][C:14]1[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])=[CH:16][S:17][CH:18]=1.C(Cl)Cl.CC(O)=O>C([O-])(O)=O.[Na+]>[Br:1][C:18]1[S:17][CH:16]=[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[C:14]=1[CH2:13][C:12]1[CH:34]=[CH:35][CH:36]=[C:10]([Cl:9])[CH:11]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cscc2Cc2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2csc(Br)c2Cc2cccc(Cl)c2)cc1
Reaction time: 16 h

Procedure:
N-Bromosuccinimide (43.0 mg, 0.242 mmol) was added to methyl 4-[(1S)-1-({[4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 3, Step 4 (50.0 mg, 0.121 mmol) in 1:1 CH2Cl2/AcOH (1.2 mL). After 16 h, the reaction was slowly poured in 5% aq. NaHCO3. The aqueous layer was extracted with CHCl3 and the combined organics were washed with 5% aq. NaHCO3, sat. Na2S2O3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (0-2% EtOAc/CHCl3 in 15 min.) to afford the desired product as a brown solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH2:43]([O:49][C:50](Cl)=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:50]([O:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:51])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CCCCCCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: CCCCCCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-59 (0.487 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]O)[C:5]([CH2:11][OH:12])=[C:4]([CH:13]=[CH2:14])[N:3]=1.[OH-].[Na+].C(=S)=[S:18]>>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][SH:18])[C:5]([CH2:11][OH:12])=[C:4]([CH:13]=[CH2:14])[N:3]=1
Reactant: C=Cc1nc(C)c(O)c(CO)c1CO
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1nc(C)c(O)c(CS)c1CO

Procedure:
Treatment of the product of Step D with sodium hydroxide and carbon disulfide by the procedure described in Example 1, Step C, yields 2-methyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethyl-6-vinylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(-c4ccccc4)c23)C1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Intermediate 1a (228 mg) obtained in Example 1-1, Step A was added with phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116 mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the mixture was refluxed by heating for 5 hours under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, then added with water (25 ml), and extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic layer was washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (158 mg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1cccc(CBr)c1C
Product: Cc1cccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-dimethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[CH2:19][CH3:20])[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][N:29]([S:37]([CH3:40])(=[O:39])=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:18](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[CH2:19][CH3:20])=[CH:34][CH:35]=1)[S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(CC)OCC
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(/CC)Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylene)-6-ethoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.3 (silica gel, methylene chloride/ethanol=5:1) C25H32N4O5S
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:10]=[CH:9]/[C:8]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1cccnc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
3-Bromopyridine (4 g, 25 mmol), methyl acrylate (2.6 g, 31 mmol), palladium(II) acetate (0.26 g, 1.2 mmol), tri-o-tolylphosphine (0.74 g, 2.4 mmol) and triethylamine (10 ml) were placed in a thick walled glass tube. The tube was sealed under argon and the mixture heated at 80° C. After 12 h the reaction mixture was allowed to cool to room temperature and chloroform (100 ml) was added. The mixture was washed with water (2×100 ml), the organics dried over anhydrous magnesium sulphate, and the solvent removed under reduced pressure. Column chromatography (flash silica gel; 1:1 ethyl acetate/hexane) yielded methyl E-3-(3-pyridyl)acrylate as a colourless oil (0.5 g, 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:39][CH:36]3[CH2:38][CH2:37]3)[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: BrCC1CC1
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OCC4CC4)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: C1(C2(CC[C:16]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[C:18]([F:29])[CH:17]=3)CC(O)=CC(=O)O2)CCCC1.[Br:30]C1C=CC(C2(C#N)CC2)=C(F)C=1>>[Br:30][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[C:18]([F:29])[CH:17]=1
Reactant: N#CC1(c2ccc(Br)cc2F)CC1
Reactant: COc1cc(C(C)(C)C#N)c(F)cc1CCC1(C2CCCC2)CC(O)=CC(=O)O1
Product: COc1cc(C(C)(C)C#N)c(F)cc1Br

Procedure:
The desired product was prepared analogously to Example A (97) step 2, substituting (4-Bromo-2-fluoro-5-methoxy-phenyl)-acetonitrile (1.95 g, 8.0 mmol) from step 4 below in place of 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile. Yield: 8.72 g, 96.0%. 1H NMR (CDCl3) δ: 1.34 (s, 6H), 3.92 (s, 3H), 7.06 (d, J=6.8 Hz, 1H), 7.33 (d, J=10.6 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28][C:29]([CH3:34])=[CH:30][C:31](=[O:33])[CH3:32]>CCO>[C:31]([C:30]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])[NH:28][C:29]=1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)C=C(C)N
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Solvent: CCO
Product: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoic acid 2-cyanoethyl ester (1.12 g, 3.00 mmol) and 4-amino-3-penten-2-one (330 mg, 3.30 mmol) in 20 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3:MeOH=5:95). 5-Acetyl-2-(4-azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (1.05 g, 77% yield).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@H:23]3[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]3)=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:18]=2)=[O:20])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NC4CCN(Cc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Yield: 77.5 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (1.0 g, 1.83 mmol) and 1-benzyl-4-piperidinylamine (2.4 ml, 11 mmol) was heated at 105° C. for 4 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (98:2, by volume) changing to dichloromethane:methanol (95:5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (1.0 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: OB(O)c1cccs1
Product: CCOc1cc(-c2cccs2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 145, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoro-methanesulphonyloxy-phenyl)-acetate by reaction with thiophene-2-boronic acid there was obtained the compound methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate, which was converted into methyl (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate hydrochloride.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1>>[CH3:22][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: Cc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
Racemic phenylalanine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([NH:22][CH3:23])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.[OH-].[K+]>O.CO>[CH3:24][N:12]1[C:13]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][CH3:23])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:26])[C:11]1=[O:25]
Reactant: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To the crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was added a solution of potassium hydroxide (100 mg) in 20% water-methanol (2 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to remove methanol. The aqueous mixture was extracted with ethyl acetate (10 ml). The extract was dried over sodium sulfate and the residue was purified by short column chromatography eluting with ethyl acetate to provide (R)-1,7-dimethyl-3-(5-hydroxyhexyl)-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 15 mg, 76% yield for 2 steps) as an oil. 1H NMR (300 MHz, benzene d6) δ 0.98 (d, 3H), 1.25-1.50 (m, 4H), 1.70-1.82 (m, 2H), 2.18 (d, 3H), 2.27 (s, 3H), 3.49-3.58 (m, 1H), 3.60 (s, 3H), 4.11 (t, 2H), 5.70 (s, 1H), 9.09 (broad s, 1H).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].I[CH2:29][CH3:30]>>[CH2:29]([N:15]1[C:16]([CH3:27])=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14]1)[CH3:30]
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC)cc2)c1C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodpropane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH2:21][CH:22]([N:28]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[NH2:28][CH:22]([CH2:21][C:10]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=[C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 1J (2.1 g, 3.82 mmol) in THF (30 mL) and H2O (30 mL) at RT was added citric acid (5 g). The reaction was stirred at RT for 1 h. After this time, no starting material was detected by LC-MS. The reaction mixture was extracted with Et2O (3×90 mL). The organic layers were combined and washed with 0.5 N citric acid (2×60 mL). The combined aqueous layers were basified to pH 8 by using 1 N NaOH (dropwise), and then extracted with Et2O (3×90 mL). The combined Et2O extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a oil (1.24 g, 84%). LC/MS (method A): retention time=2.94 min, (M+H)+=386.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:31])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][C:15]1=2.[C:32](=[O:34])=[O:33].Cl>C1COCC1>[CH3:30][O:29][C:27]([CH:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:31])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[C:20]=2[CH:19]=1)[C:32]([OH:34])=[O:33])=[O:28]
Reactant: COC(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (14.6 mmol) of diisopropylamine and 80 ml of TEP were introduced into a three-necked flask under a nitrogen stream. At -78° C., 5.8 ml (14.6 mmol) of n-butyllithium (2.5M) were added dropwise, the mixture was stirred for 30 minutes, then a solution of 3.2 g (12.2 mmol) of methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetate dissolved in 80 ml of THF was added dropwise and the mixture was stirred for one hour. While maintained at -78° C., CO2 was introduced for 30 minutes and then the temperature was permitted to increase to -40° C. and the reaction medium was poured into a 5N hydrochloric acid solution. The mixture was extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. 3.7 g (100%) of expected acid were recovered in the form of a slightly yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[S:17])SC)[CH2:6][CH2:5]1.[N-:18]=[N+:19]=[N-:20].[Na+]>O.C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:14]([SH:17])=[N:20][N:19]=[N:18]2)[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCN1CCN(CCO)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCN1CCN(CCCn2nnnc2S)CC1
Reaction time: 4 h
Yield: 28.6 %

Procedure:
To a solution of methyl N-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]-propyl]-dithiocarbamate (4.8 g) in a mixture of water (15 ml) and ethanol (10 ml) as added sodium azide (1.5 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was disolved in water and the solution was washed successively with ethyl acetate and diethyl ether and then evaporated. To the residue was added ethanol and the mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was recrystallized from isopropyl alcohol to give 1-[3-[4-(2-hydroxy-ethyl)-1-piperazinyl]propyl]-1H-tetrazole-5-thiol (1.35 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=O.CN(C)C=O.S1C=CC=C1[Cl:26]>>[Cl:26][C:2]([C:4]([F:15])([F:14])[CH:5]([O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH3:7])=[O:1]
Reactant: Clc1cccs1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
Into a 3-L vessel with a dropping funnel, added were 420 g (purity 56%, 1.25 mol) of methacrylic acid 1-hydroxycarbonyl-1,1-difluoro-2-butyl ester obtained in Example 1-3 and 7.50 g (0.11 mol/0.01 eq) of dimethylformamide. Then, 452 g (3.79 mol/0.01 eq) of thienyl chloride were dropped into the vessel at room temperature. The resulting solution was heated to 75° C. and stirred for 4 hours. The completion of the reaction was confirmed by 19F NMR. After that, the solution was distillated under a reduced pressure. With this, 255 g of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester was obtained (yield: 92%, purity: 98%).