Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:18][NH2:19])(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>C(O)C.O>[C:1]1([N:7]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:18][N:19]=[C:8]2[SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nnc(-c2ccncc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A one liter round bottomed flask, fitted with a reflux condenser, nitrogen inlet and magnetic stirrer bar, is charged with 40.5 g (0.30 mol) of phenyl isothiocyanate and 41.845 g (0.30 mol) of isonicotinic acid hydrazide in 300 ml of absolute ethanol. The mixture is heated to reflux for 3 hours. The resulting solid is filtered and washed with ethanol and then added to an aqueous solution of sodium hydroxide (prepared by dissolving 16.8 g, 0.42 mol, of sodium hydroxide in 240 ml of water). The mixture is heated to reflux for 5 hours and then stirred at ambient temperature for 18 hours. The solution is treated with 100 ml of distilled water to dissolve the gel which has formed. The solution is made acidic (to pH 2) with concentrated HCl and cooled with ice. The solid is filtered, taken up in 600 ml of warm absolute ethanol and filtered again to afford approximately 70 g (92%) of slightly wet titled product with a melting point of 288°-290° C. IR (nujol shows a peak at 1900 cm-1 ; UV (95% ethanol) shows peaks at 257 nm and 317 nm; NMR (DMSO-d6 δ) 8.5 and 7.2-7.6; the mass spectra shows a strong molecular ion peak at m/e 254, with fragment ions at 253, 195 and 149.
Reaction SMILES: C1C=CN=C(NS(C2C=CC(N=N[C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=CC=2)(=O)=O)C=1.C1C([NH2:35])=CC(C(O)=O)=C(O)C=1.C1C(N=NC2C=CC(O)=C(C(O)=O)C=2)=CC(C(O)=O)=C(O)C=1.C1C(C(NCCC(O)=O)=O)=CC=C(N=NC2C=CC(O)=C(C(O)=O)C=2)C=1>>[NH2:35][O:28][C:22]1[C:23](=[CH:24][CH:19]=[CH:20][CH:21]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(N=Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=C(O)CCNC(=O)c1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Agent: O=C(O)c1cc(N=Nc2ccc(O)c(C(=O)O)c2)ccc1O
Product: NOc1ccccc1C(=O)O

Procedure:
sulfasalazine, mesalazine, olsalazine, balsalazide, salazosulfapyridine.
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.Cl.N1C=C(CN2C3C=CC(C#N)=CC=3CN(S(C)(=O)=O)[C@H](CC3C=CC=CC=3)C2)N=C1.[C:71]1([S:77]([Cl:80])(=[O:79])=[O:78])[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.Cl.Cl.Cl.Cl.[C:85]([C:87]1[CH:88]=[CH:89][C:90]2[N:96]([CH2:97][C:98]3[N:99]=[CH:100][NH:101][CH:102]=3)[CH2:95][C@@H:94]([CH2:103][C:104]3[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=3)[N:93](S(C)(=O)=O)[CH2:92][C:91]=2[CH:114]=1)#[N:86]>>[ClH:80].[ClH:1].[C:85]([C:87]1[CH:88]=[CH:89][C:90]2[N:96]([CH2:97][C:98]3[N:99]=[CH:100][NH:101][CH:102]=3)[CH2:95][C@@H:94]([CH2:103][C:104]3[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=3)[N:93]([S:77]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)(=[O:79])=[O:78])[CH2:92][C:91]=2[CH:114]=1)#[N:86]
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1cccnc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Agent: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1)[C@H](Cc1cccnc1)CN2Cc1c[nH]cn1
Yield: 2 %

Procedure:
Example 375 was prepared as a solid in 2% yield from Compound B of Example 350 as described for Compound C of Example 350 using benzenesulfonyl chloride, and Compound D of Example 350.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1

Procedure:
Reaction of 4-trifluoromethyl-1H-imidazole (301 mg, 2.21 mmol), 95% NaH (61 mg, 2.4 mmol), and SEMCl (406 mg, 2.44 mmol) gave the title compound as a brown oil that was used without further purification. 1H NMR (CDCl3) □ 0.00 (s, 9H), 0.93 (m, 2H), 3.51 (m, 2H), 5.30 (s, 2H), 7.39 (s, 1H), 7.64 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]1[C:13](=[O:22])[N:14]([CH:19]([CH3:21])[CH3:20])[N:15]=[CH:16][C:17]=1Cl.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+].C(N(CCC)CCC)CC.Cl>>[CH3:11][C:12]1[C:13](=[O:22])[N:14]([CH:19]([CH3:20])[CH3:21])[N:15]=[CH:16][C:17]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cc1c(Cl)cnn(C(C)C)c1=O
Reactant: COc1ccc(CN)cc1
Agent: CCCN(CCC)CCC
Agent: Cl
Agent: O=C([O-])O
Product: COc1ccc(CNc2cnn(C(C)C)c(=O)c2C)cc1
Temperature: 150 °C

Procedure:
A mixture comprising 2.2 g of 4-methoxybenzylamine, 0.30 g of 4-methyl-5-chloro-2-i-propyl-3(2H)pyridazinone, 1.34 g of sodium hydrogencarbonate, 0.23 g of potassium carbonate and 5 ml of tri-n-propylamine, was heated at 150° C. for 18 hours. The reaction mixture was acidified with a 10% hydrochloric acid aqueous solution, and extracted with 60 ml of benzene. The benzene layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain an oily substance. This substance was crystallized from 5 ml of ethyl ether to obtain 40 mg of the above identified compound.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=1[O:22][C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2].Cl.N[C@H:28](C(O)=O)CS>>[CH3:28][O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=2[O:22][C:23](=[O:25])[CH3:24])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Agent: Cl
Product: COC(=O)C1CSC(c2cc(OC(C)=O)ccc2OC(C)=O)N1C(C)=O

Procedure:
The procedure described above for preparation of 3-acetyl-2-(2,5-diacetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid (5) was followed to prepare 10, except that a 2,5-dimethyl ester of L-cysteine hydrochloride was employed as starting material.
Reaction SMILES: BrC1C(O)=NC2CCN(C(=O)C(F)(F)F)CC(C)C=2C=1.O=P(Cl)(Cl)Cl.[Br:26][C:27]1[C:44]([Cl:45])=[N:43][C:30]2[CH2:31][CH2:32][N:33](C(=O)C(F)(F)F)[CH2:34][CH:35]([CH3:36])[C:29]=2[CH:28]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.CCO.CN(C=O)C>[Br:26][C:27]1[C:44]([Cl:45])=[N:43][C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]([CH3:36])[C:29]=2[CH:28]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)c(Br)cc21
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(Br)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1CNCCc2nc(Cl)c(Br)cc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
TFAA (2.5 ml) and Et3N (20 ml) was added to a solution of 3-bromo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (426 mg, 1.66 mmol) in DCM (60 ml). The mixture was stirred for 1 h at ambient temperature, concentrated in vacuo and parted between NaHCO3 and EtOAc. The organic phase was dried, concentrated and purified by column chromatography to yield 629 mg (93%) of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. MS (ESI) m/z 353.2/355.1. A mixture of 3-bromo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (629 mg, 1.78 mmol), DMF (1 ml) and POCl3 (10 ml) was heated at 100° C. for 13 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 185 mg (28%) of 3-bromo-2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.72 (s, 1H), 4.30-3.05 (m, 7H), 1.38 (d, 1.2H), 1.35 (d, 1.8H). A mixture of 3-bromo-2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (79.0 mg, 213 μmol), N2H4H2O (91.0 μl, 1.47 mmol) and EtOH (30 ml) was stirred for 16 h at room temperature. The reaction mixture was parted between EtOAc and sat. aq. NaHCO3. The organic phase was dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 45.0 mg (76%) of 3-bromo-2-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.64 (s, 1H), 3.16 (m, 2H), 3.05 (m, 3H), 2.92 (m, 1H), 2.72 (dd, 1H), 1.33 (d, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>>[CH2:1]([N:10]1[CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:20]1=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C(=C/c1ccccc1)\CNCCNc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Yield: 70.3 %

Procedure:
By treating 2.53 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine and 1.63 g of carbonyldiimidazole in the same manner as in Example 106-(2), 1.96 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([NH2:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([NH2:26])([CH3:21])[CH2:23]4)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 86.9 %

Procedure:
A mixture of 0.5 g (1.8 mmol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.34 g (2.1 mmol) of 3-methyl-3-aminoazetidine hydrochloride and 0.5 ml of triethylamine in 10 ml of pyridine is heated to reflux for 3 hours. The mixture is allowed to cool and is filtered and the product is washed with water. 0.52 g of 1-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, melting point 285°-7° C., is thereby obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCOCC1.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of 2.0 g (3.9 mmol) of methyl (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate (prepared as described in example 3.6) in 80 ml of ethanol, 30 ml of dioxane and 0.5 ml of glacial acetic acid is degassed under a nitrogen stream and then 200 mg (10% by weight) of palladium-on-carbon at 10% in suspension in 3 ml of dioxane are added. The reaction medium is placed under a hydrogen atmosphere and stirred at ambient temperature for 18 h. After filtration through celite, the filtrate is hydrolyzed and then the product is extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. 1.65 g (100%) of methyl (S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12].C[O-].[Na+].O>CO>[CH3:14][O:13][C:11](=[O:12])[C:10](=[O:15])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1ccccn1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
In an argon atmosphere at room temperature, 2-acetylpyridine (2.56 g) in methanol (26 mL) was added to dimethyl oxalate (5.00 g) and sodium methoxide (2.29 g) in methanol (26 mL), followed by stirring for 15 minutes. The mixture was stirred at 60° C. for 45 minutes, and then cooled in air. Water was added to the reaction mixture, and the resultant mixture was washed with diethyl ether. The aqueous layer was partitioned by use of saturated aqueous ammonium chloride and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(2-pyridyl)-2,4-dioxobutanoic acid methyl ester as a solid (3.44 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C:13]=3[C:12]([C:22]#[N:23])=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].C1C[O:35]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:35])[C:13]=3[C:12]([C:22]#[N:23])=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C

Procedure:
A solution of 4-(4-methoxyphenyl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (380 mg) in THF was added sodium hydride (33 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 210-212° C.;. FAB MS 395 (M+); IR (KBr) 2210 (CN), 1703 cm−1 (CO); HRMS calcd. for C26H22N2O2 394.1681 found 394, 1689.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1Cl
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-chloro-5-fluorophenyl)methanol (24, 25.5 g, 159 mmol) in dry DME (200 mL) at 0° C. was added a solution of PBr3 (25.8 g, 95.2 mmol) in dry DME (150 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at RT for another 3 h. The mixture was diluted with water (300 mL), and extracted with 1:1 petroleum-ether-EtOAc (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give 2-(bromomethyl)-1-chloro-4-fluorobenzene (25).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[F:17][C:13]1[CH:12]=[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[O:8][N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(-c2cccc(F)c2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Yield: 91.9 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylate (6.0 g, 25.51 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.21 g, 23.44 mmol, 92%) was obtained.
Reaction SMILES: CC1CCCCC1N.[CH3:9][O:10][C:11]([CH:13]1[CH2:17][C:16](=[O:18])[N:15]([CH:19]2[CH2:24][CH:23](C)[CH2:22][CH2:21][CH:20]2[CH:26](C)C)[CH2:14]1)=[O:12]>>[CH3:9][O:10][C:11]([CH:13]1[CH2:17][C:16](=[O:18])[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[CH3:26])[CH2:14]1)=[O:12]
Reactant: COC(=O)C1CC(=O)N(C2CC(C)CCC2C(C)C)C1
Agent: CC1CCCCC1N
Product: COC(=O)C1CC(=O)N(C2CCCCC2C)C1

Procedure:
1-(2-Methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester was prepared with 2-methyl-cyclohexylamine in the manner described above for 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester of Example I. 2-Methyl-cyclohexylamine (7.4 g, 47.7 mmol) was used to provide 1-(2-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (10.7 g, 38.2 mmol).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[NH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=3[Cl:35])=[O:3])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1c(Cl)cncc1Cl
Yield: 17 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 4-amino-3,5-dichloropyridine to give Compound 32 (0.06 g, 17%) as a white solid.
Reaction SMILES: [I-:1].[K+].[OH-].[K+].[F:5][C:6]([F:24])([F:23])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:12][CH2:13][O:14][CH3:15])[C:8]([F:11])([F:10])[F:9].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[F:5][C:6]([F:23])([F:24])[C:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([I:1])[CH:17]=1)([O:12][CH2:13][O:14][CH3:15])[C:8]([F:10])([F:9])[F:11]
Reactant: COCOC(c1ccc(O)cc1)(C(F)(F)F)C(F)(F)F
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CO
Product: COCOC(c1ccc(O)c(I)c1)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 76 %

Procedure:
Potassium iodide (1.24 g) and potassium hydroxide (0.46 g) were added to a mixed solution of 4-[1,1,1,3,3,3,-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]phenol (2.50 g, 8.21 mmol) in methanol (63 mL) at room temperature. Then, a 4% sodium hypochlorite solution (15.4 mL) was added in an ice bath over three hours. The mixture was returned to room temperature and stirred overnight. A 1 mol/L sodium thiosulfate aqueous solution was added to the reaction solution at room temperature, and then the pH was adjusted to 7 with 2 mol/L hydrochloric acid. After extraction with diethyl ether-water, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.44 g of the title compound (yield: 69%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([OH:19])[CH2:15][CH2:16][C:17]#[CH:18]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][OH:19])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
4-Bromobiphenyl (10.28 g, 44.10 mmol), 4-pentyn-1-ol (4.45 g, 52.92 mmol), and bis(triphenylphosphine)palladium(II) dichloride (310 mg, 0.44 mmol) were stirred in triethylamine (100 mL) under nitrogen for 5 min. Copper(I) iodide (42 mg, 0.22 mmol) was added, and the mixture was stirred for 4 hrs at 65° C. The mixture was cooled to room temperature and filtered through a celite pad, rinsed with ethylacetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (hexanes:ethylacetate 3:2) to afford 7.78 g of the title compound. Yield: 75%. 1H NMR (300 MHz, CDCl3) δ 1.88 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 7.32-7.60 (m, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.4, 31.7, 62.1, 81.2, 90.2, 122.8, 127.0, 127.1, 127.6, 128.9, 132.0, 140.1 ppm.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>C1COCC1>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]([OH:42])[C:6]2[C:7]3[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=3[N:26]=[CH:27][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:39][CH:38]=1
Reactant: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (87 mg, 0.23 mmol) in THF (5 mL) cooled to −78° C. was added LDA (2.0 M in THF, 0.6 mL, 1.15 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (64.8 mg, 0.46 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (5 mL), diluted with water (25 mL) then extracted with EA (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (64 mg, 53.6% yield) as a white solid. LCMS: [M+-THP-OH] 416 and TR=3.210 min. Used without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH:16][S:27]([CH3:26])(=[O:29])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylamine (1.60 g) is dissolved in 16 mL DCM and combined with triethylamine (2.54 mL). Then methanesulphonyl chloride (0.61 mL in 5 mL DCM) is added dropwise. The reaction mixture is stirred for 2 h and after elimination of the solvent it is purified by normal phase chromatography (cHex/EA). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.