Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCNCC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C[C@H](C)O)CC1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (100 mg. 0.148 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.445 mmol), DIPEA (115 mg, 0.891 mmol) and ethanol (5 mL) to get crude 70 mg of the titled compound. MS: m/z=695.3 (M+1).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN(C=O)C.[CH3:11][CH:12]1[CH2:18][CH2:17][N:16]2[C:19](=[O:31])[C:20]3[C:25]4[CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:24]=4[S:23][C:21]=3[N:22]=[C:15]2[CH2:14][CH2:13]1.[CH:32](Cl)(Cl)[Cl:33]>>[Cl:33][C:32]1[C:24]2[S:23][C:21]3[N:22]=[C:15]4[CH2:14][CH2:13][CH:12]([CH3:11])[CH2:18][CH2:17][N:16]4[C:19](=[O:31])[C:20]=3[C:25]=2[CH2:26][CH2:27][C:28]=1[CH:29]=[O:30]
Reactant: ClC(Cl)Cl
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCC(C=O)=C4Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
POCl3 (2.91 mmol) was added dropwise into DMF (3.02 mmol) in CHCl3 (2 ml) at 0° C. After 30 minutes compound 17 (0.36 mmol) in CHCl3 (6 ml) was added slowly dropwise. The reaction mixture was allowed to reach room temperature and stirred overnight after which the reaction mixture was heated to 50° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched with saturated NaOAc, extracted with CH2Cl2, washed with brine and water, and dried over Na2SO4. After filtration the solvent was evaporated. The product was purified by flash chromatography using CH2Cl2-EtOAc 9:1 as an eluent.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
38.3 g (277.4 mmol) of the benzene compound represented by the above formula (8) was added dropwise to a dichloromethane solution (400 ml) containing 38.8 g (291.2 mmol) of aluminum chloride and 40.9 g (291.2 mmol) of benzoyl chloride cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction product was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (19) as 41.0 g (169.2 mmol, yield of 61%) of a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]2[C:33]#[N:34])=[CH:23][CH:22]=1>CS(C)=O>[C:3]([N:8]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([CH3:18])[CH:12]=[CH:11][N:10]=1)[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]2[C:33]#[N:34])=[CH:25][CH:26]=1)(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Reactant: N#Cc1cc(Cl)cn1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(=O)N(Cc1ccc(-n2cc(Cl)cc2C#N)cc1)c1nccc(C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (114 mg, 60% oil dispersion) in dimethyl sulfoxide (5 ml) was added dropwise a solution of 2-butyrylamino-4-methyl-3-nitropyridine (605 mg) in dimethyl sulfoxide (10 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred at the same temperature for one hour and a solution of 1-(4-bromomethylphenyl)-4-chloropyrrole-2-carbonitrile (800 ml) in dimethyl sulfoxide (10 ml) was added therein. The reaction mixture was stirred at ambient temperature for 2 hours and quenched with ice water. The separated oil was extracted twice with ethyl acetate. The combined extracts were washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted by n-hexane/ethylacetate (2/1-1/1) to yield 2-[N-butyryl-N-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]amino]-4-methyl-3-nitropyridine (723 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:6][CH:5]=1)([O-])=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.[ClH:33].C1C=CC2N(O)N=NC=2C=1.Cl.C(OCC)(=O)C>CN(C=O)C>[ClH:33].[ClH:33].[N:16]1([CH2:13][CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(CCCCN2CCCCC2)cc1

Procedure:
4-(4-nitrophenyl)butanoic acid and piperidine were allowed to undergo the reaction in DMF using WSC hydrochloride and HOBt, subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to reduce the nitro group, and then reduced in the same manner as in Reference Example 2, and the resulting compound was subjected to salt formation using 4 M hydrogen chloride/ethyl acetate solution to obtain 4-(4-piperidin-1-ylbutyl) aniline dihydrochloride. F: 233.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43][C:44](=[O:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.FC(F)(F)S(O[Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])(=O)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([O:48][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH:41]6[CH:42]([O:43][C:44](=[O:46])[CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C

Procedure:
100 mg of compound (3) was dissolved in 0.7 ml of anhydrous dichloromethane and stirred together with 70 mg of dimethylaminopyridine and 49 μl of t-butyldimethylsilyl trifluoromethanesulfonate for 1 hour under cooling with ice. The reaction solution was concentrated in vacuo, dissolved in methanol, charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×22 cm) and eluted with n-hexane-ethyl acetate (4:1). The fraction containing the desired product was concentrated in vacuo to give 99 mg of compound (5) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16]2)=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1ccc(Br)c(OCC2CCC2)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2ccc(Br)c(OCC3CCC3)c2Br)CCC1

Procedure:
1.150 g (3.20 mmol) of 2,4-dibromo-3-(cyclobutylmethoxy)benzoic acid, 0.39 g (3.50 mmol) of cyclohexane-1,3-dione, 0.618 g (3.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.004 g of dimethylaminopyridine were stirred for 10 hours at room temperature in 30 ml of methylene chloride. The mixture was subsequently diluted with methylene chloride and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the combined organic phases had been dried over Na2SO4 and evaporated completely on a rotary evaporator, 3-oxo-1-cyclohexenyl 2,4 dibromo-3-cyclobutylmethoxybenzoate was obtained in the form of a yellow resin.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=S)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NC(=S)NC1=Cc1ccccc1

Procedure:
A flask equipped with a magnetic stirrer, nitrogen pressure, and reflux condenser was charged with thiohydantoin (24.9 g, 0.215 mol), benzaldehyde (22.8 g, 0.215 mol), triethylamine (43 g, 0.43 mol), and water (250 mL). Slight warming and vigorous stirring brought everything into solution. The mixture was stirred overnight and then transferred to an Erlenmeyer flask equipped with a magnetic stirrer. The pH was brought to ca. 3 with 3 M hydrochloric acid, and the mixture was stirred for 3 hr. The resulting solid was collected and washed with water and 2×50 mL of diethyl ether. The product weighed 97.6 g (97%). No other components were found in an HPLC trace at 260 and 350 nm. NMR (d6-DMSO) δ 7.2-7.8 (m, 5H), 6.4 (s, 1H), 3.5 (bs, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:15]([N:22]1[CH2:30][C:29]2([C:31]([O:33][CH3:34])=[O:32])[CH:24]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH2:30][C:29]2([C:31]([O:33][CH3:34])=[O:32])[CH:24]([C:25]([OH:41])([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH2:26][CH2:27][CH:28]2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1cccc(OC)c1)CCC2c1ccccc1
Yield: 48.5 %

Procedure:
By carrying out the reaction as in Stage A of Example 6, but from 1.56 cm3 (12.4 mmol) of 3-bromoanisole and from 302 mg (12.4 mmol) of magnesium turnings at reflux for one hour in 5 cm3 of dry diethyl ether, followed successively by 1.02 g (4.13 mmol) of anhydrous cerium chloride and by a solution of 1.5 g (4.13 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 8 cm3 of diethyl ether, 945 mg (48%) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3-methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which was as follows:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[CH3:21])(=O)=O.CCCCCCCCCCN>>[F:22][C:20]([F:23])([CH3:21])[CH2:19][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CCCCCCCCCCN
Product: COC(=O)c1ccc(OCC(C)(F)F)c(C)c1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (2.09 g, white solid) from methyl 4-hydroxy-3-methylbenzoate (1.86 g, 11.2 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.37 g, 27.9 mmol) in a similar manner to Step-1 of Amine-10.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(C2(O)C(=O)Nc3cc(Cl)ccc32)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc(C2C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
rac-6-Chloro-3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one (0.22 g, 0.84 mmol) (from Example 14a supra) was suspended in a mixture of triethylsilane (0.40 mL, 2.52 mmol) (Aldrich) and trifluoroacetic acid (1.2 mL, 12.5 mmol) (Aldrich) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 mL) and treated with solid sodium carbonate (1.0 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was triturated with dichloromethane-hexanes to give rac-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one as a white solid. (Yield 0.1 g, 50%).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1(b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a brownish solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([CH3:15])=[C:13]=[S:14].CCN(CC)CC>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([CH3:15])[C:4]2=[O:5]
Reactant: CN=C=S
Reactant: Nc1c(Br)cccc1C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=S)[nH]c2c(Br)cccc2c1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A solution of 2-amino-3-bromobenzoic acid (Maybridge, Trevillett, UK; 3.03 g, 14.02 mmol) and isothiocyanatomethane (Aldrich; 1.151 mL, 16.82 mmol) in EtOH (28 mL) was stirred at 75° C. for 3.5 d. Additional isothiocyanatomethane (2.302 mL, 33.64 mmol) and Et3N (2.74 mL, 19.63 mmol) were added, and the resulting mixture was stirred at 75° C. for 1 d. The mixture was concentrated in vacuo and the residue was triturated with Et2O (40 mL) to provide 8-bromo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2.90 g, 10.70 mmol, 76% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (1H, br. s.), 8.11 (1H, d, J=8.0 Hz), 7.85 (1H, dd, J=7.9, 1.3 Hz), 7.20 (1H, t, J=7.9 Hz), 3.83 (3H, s). m/z (ESI, +ve) 271.0 (M+H)+.
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39].O>C1COCC1>[CH:38]([C:41]1[CH:42]=[C:43]([CH:47]([CH3:51])[CH2:48][CH:49]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH3:13])[CH:44]=[CH:45][CH:46]=1)([CH3:40])[CH3:39]
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCC(C)c1cccc(C(C)C)c1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.6 %

Procedure:
A solution of 1-(2-naphthyl)ethyltriphenylphosphonium bromide (2.30 g, 4.62 mmol, 1.0 equiv.) in THF (16 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 2.9 mL, 4.62 mmol, 1.0 equiv.) at 0° C., the red-brown suspension was stirred at 0° C. for 15 min. 3-(3-Isopropylphenyl)butanal (1.32 g, 6.94 mmol, 1.5 equiv.) in THF (2 mL) was added, and the mixture was stirred at 0° C.→70° C. for 18 h. After addition of H2O, the aqueous layer was extracted with hexanes (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3) to yield 0.57 g (38%) of the title compound as a colorless viscous oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (442 mg, 1.19 mmol) (obtained as described in Reference Example 40(4)) in methylene chloride (15 ml) were added methanesulfonyl chloride (0.12 ml, 1.49 mmol) and triethylamine (0.20 ml, 1.49 mmol) in an ice bath. The mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with 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 hexane:ethyl acetate (1:2) as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (517 mg, yield 97%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C)C=O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH:10]2[CH2:9][NH:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([OH:22])[C:5]=3[CH2:11]2)=[CH:15][CH:16]=1)=[O:21])[CH3:43]
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Reactant: CCOC(=O)CN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)c1ccc(CCC2CNc3nc(N)nc(O)c3C2)s1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 37.8 %

Procedure:
To 0.15 g (0.47 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.0 mL of anhydrous dimethylformamide and 0.11 mL (0.99 mmol) of 4-methylmorpholine. To this was then added 0.84 g (0.48 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The reaction mixture was stirred at room temperature for 35 minutes and a solution of 0.072 g (0.51 mmol) of glycine ethyl ester hydrochloride in 1.0 mL of anhydrous dimethylformamide was added together with 0.65 mL (5.85 mmol) of 4-methylmorpholine. After 35 minutes, an additional 0.015 g (0.11 mmol) of glycine ethyl ester hydrochloride and 0.2 mL (1.80 mmol) of 4-methylmorpholine was added. The reaction was stirred for 3 hours and concentrated in vacua. The crude mixture then was chromatographed on silica gel eluting with a gradient of 2-12% CH3OH/CHCl3 to give 0.072 g (38%) of N-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}glycine ethyl ester as a white solid. Rf=0.34 (20% CH3OH/CHCl3) m.p.=152°-160° C. (foam, dec.) Mass Spectrum (FD+): M+=405; IR (CHCl3, cm-1)=1046, 1196, 1304, 1464, 1602, 1745, 2363, 2977, 3025, 3619; UV (C2H5OH) λmax =222, 279 (ε=24333, 23816); 1H NMR (300 MHz, DMSOd6) δ1.17 (t, J=6.5 Hz, 3H), 1.52-1.60 (m, 3H), 1.77-1.84 (m, 1H), 2.40-2.44 (m, 1H), 2.72-2.8(m, 3H), 3.14-3-24 (m, 1H), 3.91 (d, J=4.7 Hz, 2H), 4.05-4.12 (m, 2H), 6.24 (s, 2H), 6.89 (s, 1H, 7.57 (s, 1H), 8.80 (s, 1H), 9.66 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]2=[O:17])=[CH:9][CH:8]=1)(=O)=O.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[C:20]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=C1CCCc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
While stirring a mixture comprising 15.32 g (52.06 mmol) of 7-trifluoromethanesulfonyloxy-3,4-dihydro-1(2H)-naphthalenone obtained in the Synthesis Example A-1, 12.7 g (104.12 mmol) of phenylboric acid, 10.8 g (78.09 mmol) of potassium carbonate and 450 ml of toluene at room temperature, nitrogen gas was bubbled thereinto for 30 minutes. Next, 1.81 g (1.57 mmol) of tetrakistriphenylphosphine palladium was added thereto. The mixture was slowly heated to thereby maintain the bulk temperature at about 90° C. After stirring at this temperature for 90 minutes, the reaction mixture was cooled and water was added thereto. The insoluble matters were filtered through celite and thoroughly washed with ethyl acetate. The organic phase was collected, washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N hydrochloric acid, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After successively eluting with hexane:ethyl acetate in a ratio ranging from 20:1 (v/v) to 12:1 (v/v), 9.53 g of the title compound was obtained as white crystals. Yield 82%.