Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].[CH3:8][C:9]1[N:14]=[C:13]([NH:15][C:16](=[S:18])[S-:17])[CH:12]=[CH:11][CH:10]=1.C([NH+](CC)CC)C.C1CCCCC1>C(#N)C>[OH:7][C:3]1([CH2:4][CH2:5][CH3:6])[CH2:2][S:18][C:16](=[S:17])[N:15]1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:8])[N:14]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CCCC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: C1CCCCC1
Product: CCCC1(O)CSC(=S)N1c1cccc(C)n1
Temperature: 10 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
1-Chloropentan-2-one (12.1 g) is added to a suspension of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (28.5 g) in anhydrous acetonitrile (200 cc) at a temperature between 15° and 25° C. The reaction is continued for 2 hours at 20°-25° C. The insoluble triethylamine hydrochloride is removed by filtration and washed twice with diethyl ether (60 cc. total). The solvents are evaporated under reduced pressure (20 mm.Hg) at 40° C. The residual oil is dissolved in a mixture of diethyl ether (100 cc) and methylene chloride (50 cc); the organic solution is washed twice with distilled water (total 100 cc), dried over sodium sulphate and evaporated. The crystals obtained (25.4 g; m.p. about 70° C.) are dissolved in boiling cyclohexane (500 cc) and the boiling solution is filtered. After cooling for 1 hour at about 10° C., the resulting crystals are separated by filtration, washed twice with cyclohexane (total 120 cc) cooled to 10° C., and dried under reduced pressure (0.1 mm.Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-4-propylthiazolidine-2-thione (21.6 g), melting at 83° C., is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[CH3:42][O:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>ClCCl>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([N:47]3[CH2:48][CH2:49][CH:44]([O:43][CH3:42])[CH2:45][CH2:46]3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC1CCNCC1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COC1CCN(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
To a cooled (0° C.) solution of N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4l, 0.200 g, 0.506 mmol) in dichloromethane (4 mL) was added 4-nitrophenyl chloroformate (0.111 g, 0.551 mmol) as a solid. After 10 min the reaction was allowed to warm to room temperature. After 3 h 4-methoxy-piperidine (0.100 mL, 1.036 mmol) was added dropwise via syringe and the reaction was stirred overnight. The reaction was evaporated onto silica gel and purified by flash chromatography (Isco, 25 g) eluting with (25% EtOH/EtOAc):hexanes (0:1→2:3) to give N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamide (166 mg. 61% yield) of a clear, colorless tar. MS m/z=537 [M+H]+. Calculated for C26H28F4N4O4: 536
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]2[N:43]([CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[O:41][N:40]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:42](=[O:50])[O:41][N:40]=3)=[CH:29][CH:28]=2)[C:7]1=[O:18]
Reactant: COCCOCn1c(-c2ccccc2-c2ccc(CBr)cc2)noc1=O
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-4-[(2-methoxyethoxy)methyl]-1,2,4-oxadiazol-5(4H)-one (14.5 g), potassium carbonate (8 g) and acetonitrile (500 mL) was stirred at 50° C. for 4 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (15.5 g, 79%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:4][N:3]1[C@H:2]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:7][C:6]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[CH:5][C:19]=3[CH2:20][CH2:11]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1ccc2ccccc2n1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5n4)cc3CC[C@@H]12
Yield: 54 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 126 mg (54%) of the title compound as an amorphous foam. mp 140°-145°. FDMS: m/e=356. α[D]589 =+74.01 (c=0.46, chloroform).
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1.Cl[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)(O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCCC(C)(C)O)c(=O)c2c1ncn2CC(O)CO
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 18 g (0.075 mol) of the xanthine compound from stage (a), 12.5 g (0.083mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 11.5 g (0.083 mol) of potassium carbonate in 500 ml of dimethylformamide is stirred for 18 hours at 110° C., after which the hot mixture is filtered and the filtrate is concentrated in vacuo. The oily crude product, which gradually crystallizes through, can advantageously be purified by filtration over a silica gel column using a chloroform/methanol (10:1) solvent mixture, followed by a final recrystallization from ethyl acetate with the addition of petroleum ether, at the boil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH3:16])[C:5]=2[N:6]=1.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]([O:25][CH2:26][C:27]1[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:45])([F:44])[F:43])=[N:29][O:30][C:31]=1[CH:32]1[CH2:34][CH2:33]1)[CH2:18]2.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:32]1([C:31]2[O:30][N:29]=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:43])([F:44])[F:45])[C:27]=2[CH2:26][O:25][CH:19]2[CH2:18][CH:17]3[N:24]([C:2]4[S:3][C:4]5[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH3:16])[C:5]=5[N:6]=4)[CH:21]([CH2:22][CH2:23]3)[CH2:20]2)[CH2:33][CH2:34]1
Reactant: COC(=O)c1cc(OC)c2nc(Cl)sc2c1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(OC)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 120 °C
Yield: 53.3 %

Procedure:
The ester, methyl 2-chloro-4-methoxybenzo[d]thiazole-6-carboxylate (124 mg, 0.48 mmol) and 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (200 mg, 0.48 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol) were sequentially dissolved in dimethylacetamide (1 mL) and heated to 120° C. overnight. The reaction mixture was allowed to cool to room temperature and then diluted with ethyl acetate and aqueous saturated sodium bicarbonate solution. The organics were separated, the aqueous layer was subjected to a further wash with ethyl acetate, and the organics were combined and dried (MgSO4) then evaporated in vacuo. The product was purified by silica gel chromatography with a gradient of 0-100% ethyl acetate/hexanes to furnish 161 mg of a clear oil that was used directly in the following transformation without further manipulation.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([CH3:18])[CH2:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.[C:23]([O-])(O)=[O:24].[Na+]>CO>[OH:14][C:15]1[CH:16]=[C:7]([OH:6])[CH:8]=[CH:9][C:10]=1[CH:11]([CH3:18])[CH2:12][C:13]([O:24][CH3:23])=[O:17]
Reactant: CC1CC(=O)Oc2cc(O)ccc21
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (1.2 mL, 43 mmol) was added to a solution of 7-hydroxy-3,4-dihydro-4-methylcoumarin (B1) (75.8 g, 430 mmol) in methanol (1 L) at room temperature and the solution stirred for about 16 hours. At this time, TLC (8% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was neutralized with 7% NaHCO3 solution (50 ml) and the majority of the solvent (750 ml) removed under reduced pressure. The solution was diluted with ethyl acetate (1 L), washed successively with saturated NaHCO3: saturated NaCl (1:1, 200 ml), saturated NaCl (2×200 ml), dried (Na2SO4), filtered and the solvent removed to give an orange oil. Further purification by filtering through a short pad of silica gel and eluting with 5% methanol in chloroform afforded pure product as a pale orange gel (87 g, 98%): 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.42 (dd, JJ=15.0, 8.9, 1H), 2.58 (dd, JJ=15.0, 5.8, 1H), 3.37 (m, 1H), 3.55 (s, 3H), 6.15 (dd, JJ=8.6, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 8.93 (s, 1H), 9.11 (s, 1H); 13C NMR (DMSO-d6) d 20.16, 29.09, 40.77, 51.00, 102.55, 106.02, 122.09, 127.04, 155.18, 156.27, 172.55; m/z (EI; TMS derivatized; M+) 354; IR (neat; cm−1) 3384.5, 2969.3, 1708.9, 1621.0, 1606.3, 1518.4, 1454.9, 1367.0, 1303.5, 1220.4, 1166.7, 1108.1, 976.2, 839.4, 810.1.
Reaction SMILES: C([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([O:30]CC)=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])[CH2:6]1)(=O)C.[ClH:35]>>[ClH:35].[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([OH:30])=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])[CH2:6]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 84 %

Procedure:
In 5 ml of 6N hydrochloric acid was dissolved 500 mg of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction under reflux for 4 hours. Subsequently, the crystals thus deposited were collected by filtration and washed with 1 ml of water to obtain 390 mg (yield 84.0%) of 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride having a melting point 247°-250° C. (decomp.). The physical properties of this compound were identical with those of the compound obtained in Example 54.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:30][CH2:31][CH3:32]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH2:30][CH2:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCc1ccc(S(C)(=O)=O)cc1I
Product: CCCc1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-4-(methylsulfonyl)-1-propylbenzene (Intermediate 62), the title compound was obtained as a white solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>CN(C)C=O>[CH2:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
Benzyl chloride (5.5 ml, 47.8 mmol) and potassium carbonate (8.3 g, 60.1 mmol) were added to a solution of ethyl 3-piperidinecarboxylate (6.55 g, 40.0 mmol) in N,N-dimethylformamide (20 ml), and the resulting mixture was stirred at 100° C. for 10 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was subjected to azeotropic concentration with toluene. The resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1) to obtain ethyl 1-benzyl-3-piperidinecarboxylate (7.45 g, 75.3%).
Reaction SMILES: Cl.[Si:2]([O:19][C@H:20]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[C@H:21]1[CH2:26][CH2:25][CH2:24][NH2+:23][CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(OCC)(=O)C>CO.O>[Si:2]([O:19][C@H:20]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[C@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](O[C@H](c1nccs1)[C@H]1CCC[NH2+]C1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](O[C@H](c1nccs1)[C@H]1CCCNC1)(c1ccccc1)c1ccccc1

Procedure:
30 ml of hydrogen chloride (4 M in 1,4-dioxane) were added dropwise at +5° C. to a solution of 1.08 g (2.0 mmol) of tert-butyl (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]-piperidine-1-carboxylate in 30 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. Evaporation gave 1.03 g of (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-yl-methyl]piperidinium hydrochloride; HPLC/MS (M+H)+=437; rotation value in methanol [α]20D=−18.1°. The hydrochloride was dissolved in 10 ml of water, cooled in an ice bath, and 1 ml of sodium hydroxide solution (2 M) was added dropwise. The precipitate was taken up with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sufate, filtered and evaporated, giving 0.8 g of (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]piperidine as amorphous resin; HPLC/MS (M+H)+=437; rotation value in methanol [α]20D=−22.1°. 1H NMR (400 MHz, DMSO) δ 7.69-7.56 (m, 4H), 7.52-7.38 (m, 6H), 7.38-7.26 (m, 2H), 4.84 (d, J=6.6, 1H), 4.03 (q, J=7.1, 1H), 2.94 (d, J=11.2, 1H), 2.73 (d, J=11.8, 1H), 2.25-2.10 (m, 2H), 1.78 (dtd, J=10.5, 6.9, 3.3, 1H), 1.49-1.30 (m, 2H), 1.19-1.10 (m, 2H), 1.04-0.93 (m, 9H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.[OH-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:1][N:2]=[N:3]1.[CH3:16][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4]1
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccc(Br)cn2)n1
Product: Cn1nnnc1-c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodiumhydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=N)OCC)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:18]#[N:19]>CO>[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]2[N:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:22]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[N:14]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=N)c1ccc(O)cc1
Reactant: N#Cc1ccc(NC2CCCCC2)c(N)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of ethyl 4-hydroxybenzimidate hydrochloride (5, 1.26 g, 6.7 mmol) and compound 4 (1.5 g, 5.0 mmol) in methanol (10 mL) was refluxed overnight under a nitrogen atmosphere. The reaction mixture was cooled to rt, filtered, and washed with methanol to afford 6 as a pinkish brown solid (1.26 g, 68%). ESI-MS m/e 372.1 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C#Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (300 mg, 747 μmol) and 4-(dimethylamino)pyridine (13.8 mg, 113 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11p (291 mg, 448 μmol, 60.0%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.10 (s, 6H), 0.20 (s, 6H), 0.90 (s, 9H), 0.93 (s, 9H), 3.65 (s, 2H), 6.63-6.73 (AA′BB′, 2H), 6.92-7.02 (AA′BB′, 2H), 7.17-7.27 (AA′BB′, 2H), 7.33-7.48 (m, 5H), 7.96-8.05 (AA′BB′, 2H), 8.99 (s, 1H), 10.69 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.60 (2C), −4.61 (2C), 17.8, 17.9, 25.5 (6C), 41.7, 85.8, 94.5, 119.5 (2C), 120.4 (2C), 121.2, 128.2, 128.28 (2C), 128.34, 128.6 (2C), 129.5, 130.3 (2C), 131.8 (2C), 133.1, 138.5, 146.6, 148.0, 153.8, 156.9, 169.4; IR (KBr, cm−1) 530, 689, 756, 781, 839, 914, 1007, 1125, 1169, 1258, 1379, 1433, 1510, 1605, 1672, 2214, 2857, 2930, 2955, 3235.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: Oc1ccc2ncccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4ncccc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 89.9 %

Procedure:
Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (74 mg, 0.23 mmol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxyquinoline (41 mg, 0.28 mol) to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazoline (89 mg, 94%).