Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:10])=[CH:13][CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Nc1nccs1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.4 mmol) in DCM (10 ml) was added triethylamine (0.23 ml, 1.68 mmol) and HOBt (0.23 g, 1.68 mmol) at 0° C. After stirring at this temperature for 5 min. added 2-aminothiazole (0.168 g, 1.68 mmol) and followed by EDCI (0.332 g, 1.68 mmol). The resulting solution was stirred for 12 h. then quenched with saturated aqueous NH4Cl solution (15 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL). The organic phase was successively washed with 2% HCl (50 mL), brine (50 mL) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:10 ethyl acetate:hexanes) to give 2-(4-Chloro-phenoxy)-2-methyl-N-thiazol-2-yl-propionamide (0.325 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.58 (s, 6H), 6.76 (d, J=8.8 Hz, 2H), 7.01 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.50 (d, J=3.6 Hz, 1H), MS (EI) m/z 296.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)=[CH:33][CH:34]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:40]1[CH:41]=[C:37]([CH2:36][O:35][C:32]2[N:31]=[N:30][C:29]([N:14]3[CH2:13][C:12]4[CH2:8][N:9]([C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=4[CH2:15]3)=[CH:34][CH:33]=2)[N:38]=[CH:39]1
Reactant: Clc1ccc(OCc2cscn2)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCc3cscn3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol) was reacted analogously to example 4b with 3-chloro-6-(thiazol-4-ylmethoxy)pyridazine (287.3 mg, 1.26 mmol). Yield: 36 mg (5%), M+H+: 474.26.
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:43]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52](O)=[O:53])([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].Cl.CN(C)CCCN=C=NCC>ClCCl>[Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:42])[C@:16]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:52]([C@@H:51]5[CH2:55][CH2:56][CH2:57][N:50]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:53])=[C:26]([CH3:32])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C[n+]2cnn(C[C@](O)(c3ccc(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81 %y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(RoO9-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79%y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA-dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Reaction time: 1 h

Procedure:
(3S,9aR)-tert-Butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (3.00 g, 7.99 mmol) was dissolved in TFA (10 mL) and stirred for 1 hr. The trifluoroacetic acid was removed under reduced pressure and azeotroped with dichloroethane (3×) then was dried over high vacuum to yield the title compound: LC-MS (IE, m/z): 276 [M+1]+; 1H-NMR (500 MHz, DMSO) δ ppm 7.755 (dd, J=8.75, 6.2 Hz, 1H), 7.38 (t, J=8.85 Hz, 1H), 4.80 (d, J=10.1 Hz, 1H), 3.98 (dd, J=11.25, 2.5 Hz, 1H), 3.456 (t, J=10.7 Hz, 1H), 3.354 (d, J=12.6 Hz, 1H), 3.273 (d, J=11.8 Hz, 1H), 2.984-3.089 (m, 3H), 2.715 (t, J=11.37 Hz, 1H), 2.639 (t, J=10 Hz, 1H), 2.50 (s, 3H), 2.46 (b, 1H), 2.337 (t. J=10.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(F)cc1F

Procedure:
The title compound was prepared from 2-(2,4-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.54 (2H, s), 3.76 (3H, s), 3.86 (2H, s), 6.83-6.90 (2H, m), 7.13-7.19 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[CH:9][C:8]2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:19]([O:21][CH2:22][CH3:23])=[O:20].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)cc3c2n1CCCCC3=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(Cl)c(O)cc3c2n1CCCCC3=O
Temperature: -20 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of ethyl 5,6,7,8-tetrahydro-11-chloro-10-methoxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate (4.00 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to -78° C., and boron tribromide (3.26 g, 13.0 mmol) was added dropwise. The reaction temperature was raised to -20° C. and the reaction mixture was stirred at -20° C. for 8 hours. The reaction mixture was poured into ice water and extracted three times with ethylacetate, and the extract solution was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 0.99 g of ethyl 5,6,7,8-tetrahydro-11-chloro-10-hydroxy-8-oxo-4H-azocino[3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[C:37](=[O:39])=[O:38]>C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:37]([OH:39])=[O:38])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl ]-4-methylpyridine (1.39 g, 3.28 mmol) obtained in Example 10 in toluene (60 ml), a hexane solution of n-butyllithium (1.54 M, 2.55 ml, 3.93 mmol) was added in an argon atmosphere at −78° C. After stirring for 1 hour at the same temperature, carbon dioxide was bubbled thereinto the mixture. The reaction mixture was allowed to warm to room temperature over 2 hours, subsequently 0.1 N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with methylene chloride:methanol=10:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol, diethyl ether and hexane, and was collected by filtration, to obtain the title compound (815 mg, 2.09 mmol, 64%) as a white solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@@H:4]3[CH2:7][C@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1N[C@@H]2CC[C@H]1C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 71.6 %

Procedure:
To a solution of ethyl (1R, 3S, 4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.724 g, 4.28 mmol) in chloroform (8 ml) was added triethylamine (0.60 ml, 4.28 mmol) and 4-methoxybenzenesulfonyl chloride (0.973 g, 4.71 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1R, 3S, 4S)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.04 g, 71%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>C(N(CC)CC)C>[S:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In 100 ml of triethylamine was dissovled 76 g (1.0 mole) of 1,3-propanediol, and 95 g (0.50 mole) of tosyl chloride was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 800 ml of dichloromethane was added to the residue. The resulting mixture was washed with 150 ml of water, 120 ml of 1N hydrochloric acid and 150 ml of water, successively, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography of silica gel (600 g), and eluted with dichloromethane-methanol (96:4). The desired fracticns were concentrated under reduced pressure to give 1,3-propanediol monotosylate as a colorless oily material. Yield 86.9 g (yield: 78%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Br:35].O.[OH-].[Na+].Cl>CO>[Br:35][C:7]1[CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc(-c2ccc(OCC(=O)OC)c(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc(-c2ccc(OCC(=O)O)c(Br)c2)cc1
Yield: 88.3 %

Procedure:
Methyl{[3-bromo-4′-({[(2-butyl-1-benzofuran-3-yl)carbonyl]amino}methyl)[1,1′-biphenyl]-4-yl]oxy}acetate (314 mg, 0.57 mmol), prepared in the previous step, in 100 mL of methanol and 10 mL of water was warmed to dissolve the solid. While still warm 1 N NaOH (684 μL, 0.68 mmol) was added and the mixture stirred, with no additional heat, until the reaction was complete by TLC. The reaction was acidified by the addition of 715 μL of 1 N HCl and then concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound as a light tan solid (270 mg, 87%), mp 175-190° C. Elemental Analysis for C28H26BrNO5.0.40 H2O. Calc'd: C, 61.87; H, 4.97; N, 2.58. Found: C, 61.35; H, 4.54; N, 2.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCc1ccccc1
Product: Brc1cccc(OCc2ccccc2)n1
Yield: 76 %

Procedure:
2,6-Dibromopyridine was condensed with benzyl alcohol by Ullmann reaction to obtain 2-benzyloxy-6-bromopyridine (yield 76%). This was further condensed with m-cresol by Ullmann reaction to obtain 2-benzyloxy-6-(3-methylphenoxy)-pyridine (yield 83%), which was then subjected to catalytic reduction in the presence of a catalyst, 5% palladium-carbon, to obtain 6-(3-methylphenoxy)-2-pyridone (yield 96%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.C[Si](Br)(C)C.C(Cl)[Cl:18]>>[Cl:18][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: ClCCl
Reactant: O=c1[nH]cnc2ccccc12
Agent: C[Si](C)(C)Br
Product: Clc1ncnc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL) was added TMSBr (0.079 mL, 0.61 mmol) at 0° C. The reaction was stirred for 1 h at 0° C., then for 1 h at RT. The reaction was quenched with water (3 mL) and stirred for 15 min. The aqueous layer was washed with EtOAc (5 mL), and dried with lyophilizer overnight to give desired product 3 as white foam (0.14 g, 100% yield). LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([CH3:20])=[CH:17][CH2:18]Br>O1CCCC1>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH:17]1[C:16]([CH3:20])=[CH2:15])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(=CCBr)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1CC1(C#N)C(=O)OC
Yield: 102.3 %

Procedure:
A mixture of 65.3 g of methyl cyanoacetate, 228 g of freshly pulverized potassium carbonate and 800 ml of anhydrous tetrahydrofuran was heated at reflux under nitrogen for 2 hours. A solution of 150.5 g of 1,4-dibromo-2-methyl-2-butene in 500 ml of anhydrous tetrahydrofuran was added slowly dropwise to the refluxing reaction mixture over a period of two days. The solids were removed from the cooled reaction mixture by filtration through a bed of celite. The filtrate was concentrated in vacuo to leave 111.4 g of yellow oil. Distillation of the oil gave 81.3 g of the desired product as a colorless oil: b.p. 95°-105° C. (0.05 mm Hg) consisting of two isomers in a ratio of 2:1 by GLC.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19]([O:20]CC)=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:17]=[N:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:28](I)[CH3:29]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:16]([CH2:28][CH3:29])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C(C)=O)CC3)ncc2c1OCC
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-acetyl-1-piperazinyl)-5-ethoxypyrido[2,3-d] pyrimidine-6-carboxylate with ethyl iodide, there is obtained the product, m.p. 208° - 210°C with decomposition.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:25]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=2)[CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>>[CH3:24][C:10]1[CH:9]=[C:8]([C:25]2[N:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[O:27][N:26]=2)[CH:7]=[C:6]([CH3:5])[C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:4][N:3]=[C:1]([CH3:2])[CH:23]=1
Reactant: C#CCCCCCCCCCOc1c(C)cc(-c2noc(C(F)(F)F)n2)cc1C
Reactant: CC=NO
Product: Cc1cc(CCCCCCCCCOc2c(C)cc(-c3noc(C(F)(F)F)n3)cc2C)on1

Procedure:
Following Procedure 1 and using equivalent amounts of acetaldehyde oxime and 3-[3,5-dimethyl-4-(9-ethinylnonyloxy)phenyl]-5-trifluoromethyl-1,2,4-oxadiazole, there can be obtained 5-{9-[2,6-dimethyl-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenoxy]nonyl}-3-methylisoxazole [I; R1 =CH3, Y=(CH2)9, R2 and R3 =2,6-(CH3)2, R4 =CF3 ].
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2
Reactant: CS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of 0.20 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 47 mg of methylmercaptan sodium salt and 6 ml of DMF was stirred for 1 hour under ice cool. To this mixture was added 47 mg of methylmercaptan sodium salt, and the resultant mixture was stirred further for 1 hour under ice cool. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.19 g of 2-[3-(methylthio)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 14).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([C:15]([N:17]1[CH2:22][C@@H:21]2[CH2:23][C@H:18]1[CH2:19][N:20]2C(OC(C)(C)C)=O)=[O:16])[NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C@H:18]12[CH2:23][C@H:21]([NH:20][CH2:19]1)[CH2:22][N:17]2[C:15]([C@@H:3]([NH:4][C:5](=[O:6])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]([CH3:31])([CH3:1])[CH3:32])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H]2C[C@H]1CN2
Yield: 94.7 %

Procedure:
A solution of 1,1-dimethylethyl (1S,4S)-5-(3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.5 g, 5.5 mmol) in 30 ml TFA/DCM (20%) was stirred at room temperature for 1 h. The reaction mixture was made basic by addition of sodium hydroxide, then extracted with DCM (3×50 mL). The DCM was dried over anhydrous Na2SO4 and concentrated to give the title compound (1.8 g) as a pale brown oil. LCMS (m/z): 346.1 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8](Cl)[C:7]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].[OH2:23]>>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:23])[C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: O
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Yield: 74 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, (N-isoxazolidinyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.08 g, 3.3 mmol), 80% NaH (0.3 g, m10.0 mol) and water (72 μL, 4 mmol) were reacted to form the desired product (0.79 g, 77%). LC-MS m/z 309(M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18]>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:19][CH2:16][C:17]#[CH:18])[C:6]1=2
Reactant: C#CCN
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Reaction time: 16 h

Procedure:
To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargyl amine (3.0 g), the solution was stirred at room temperature under a nitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was added in a dropwise manner. The mixture was stirred for 16 hours before quenching with ice water. The mixture was filtered, the solids were washed with CH2Cl2, the layers were separated and the organic portion was dried (Na2SO4). After concentration, the crude product was purified via flash chromatography eluting with hexane/acetone (2:1) to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.