Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])[N:23]4[N:22]=3)=[C:16]([O:38][CH3:39])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[N:23]2[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][C:16]=3[O:38][CH3:39])=[N:22]2)=[CH:27][CH:28]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 95.6 %

Procedure:
4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (650.00 mg, 1.227 mmol) was treated with trifluoroacetic acid (0.473 mL, 6.136 mmol) in methylene chloride (3 mL) at room temperature until complete reaction of starting material was observed by hplc analysis of reaction mixture. The reaction was quenched with minimum amount of saturated aqueous sodium carbonate, and was extracted extensively in dichloromethane. The combined organic extracts were dried over MgSO4 and then filtered. Evaporation of solvent under reduced pressure afforded [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine as a yellow foam (504 mg, 96%) which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]#[N:33])=[C:27](B(O)O)[CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:21])[CH:3]=2)[CH:24]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)C(Cc1ccccc1)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccccc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
572 mg (1.6 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate (racemate) and 330 mg (1.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 300 mg (purity 94%, 43% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH2:11][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CCO
Product: O=C(CCN1CCCC1)Nc1ccc(Br)cc1

Procedure:
N-(4-Bromo-phenyl)-acrylamide (0.3 g, 1.33 mmol) was dissolved in ethanol. Pyrrolidine (0.12 ml, 1.46 mmol) was added and the mixture was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. Aqueous ammonium chloride was added and the aqueous layer was extracted twice with ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the desired product. Yield 0.24 g, 60%. LCMS method: 2, RT: 2.67 min; MI: 297-299 [M+1].
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][C:7]([CH3:34])=[N:6]1)(C)(C)C>C(O)=O.C(Cl)Cl>[CH3:34][C:7]1[CH:8]=[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)[NH:5][N:6]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1
Solvent: O=CO
Solvent: ClCCl
Product: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)[nH]n1
Temperature: 95 °C
Yield: 57.6 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-phthalazin-1-one (0.012 g, 0.026 mmol) was dissolved in formic acid (1 ml) and heated at 95° C. for 4 h. The resulting raw product was dissolved in DCM, after evaporation of formic acid. Extraction with a saturated aqueous NaHCO3 solution, combining of the organic phases, evaporation of the solvent in vacuum and purification by chromatography over silica gel with DCM:MeOH (20:1) yielded the title compound (0.006 g, 57%). 1H-NMR: (400 MHz, D6-DMSO) 11.81 (1H, s), 9.21 (1H, s), 8.48 (1H, d), 8.35 (1H, d), 7.87-7.96 (2H, m), 7.50 (2H, d), 7.01 (2H, d), 6.25 (1H, s), 3.21 (4H, m), 2.19 (3H, s), 1.64 (4H, m), 1.60 (2H, m); MS (ESI+)=401.29 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]3[N:19](S(C4C=CC=CC=4)(=O)=O)[C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[OH-].[Na+]>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1cc2cc([N+](=O)[O-])ccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 115 %

Procedure:
A solution of N-phenylsulfonyl-5-nitroindol-2-yl 2-[1-(phenylmethyl)-4-piperidinyl]ethyl ketone (160 mg, 0.32 mmol) in 3 ml of methanol and 2 ml of 2N NaOH was heated at reflux for 2 hours. The mixture was concentrated to dryness and the residue was diluted with brine and extracted with chloroform. The organic layer was dried and concentrated to dryness to give 144 mg of a brown solid which was purified through silica gel column chromatography to give 31 mg of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[CH2:6][CH2:5]2.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c([N+](=O)[O-])cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc2c(cc1Cl)CCC2=O
Reaction time: 4 h

Procedure:
114 Grams (2.01 moles) of iron powder are added to a solution of 134 g (0.64 mole) of 5-chloro-6-nitro-1-indanone in 1600 ml of ethanol, then 63.5 ml of concentrated hydrochloric acid are added dropwise, and the reaction mixture is boiled for 4 hours. The precipitate is filtered off with suction, and the product is precipitated from the hot filtrate by the addition of water, then suction-filtered and washed with water. The residue of the reaction mixture is boiled with chloroform, the filtrate is dried with Na2SO4 and is then concentrated to dryness, after which process a further amount of the product is obtained. The substance melts at a temperature of from 198° to 200° C., and after recyrstallization from ethanol the melting point is in the range of from 203° to 205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([NH:26][CH3:27])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:30]N(C=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([N:26]([CH3:30])[CH3:27])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1

Procedure:
[11C]MeI (from Step 1) was trapped in a RT mixture of (1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)-N-methylcyclopropane-carboxamide (product of Example 6, 0.25 mg) in DMF (0.25 mL) containing 16 ul of NaH (0.5 g/20 mL DMF). The reaction mixture was transferred to a 2 mL v-vial at 65° C., heated for 5 minutes, diluted with H2O (0.8 mL) and injected onto the HPLC (Gemini C18, 10×150 mm, Phenomenex). The desired peak was eluted with a solvent system containing 25% A and 75% B (A=MeCN, B=95:5:0.1H2O:MeCN:TFA, 5 ml/min, retention time ˜6.5 minutes) and collected in a heated round bottom flask on a rotary evaporator. The solution was concentrated and vacuum transferred to a septum capped 5 mL v-vial. The round bottom flask was rinsed with ethanol (0.1 mL) and saline (1-2 mL) and vacuum transferred to the same v-vial to give 13.6 mCi of [11C] (1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)-N,N-dimethyl-cyclopropanecarboxamide.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)O1.Br[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1>>[C:20]([O:19][C:17]([C:16]1[CH:24]=[C:25]([C:28]([F:31])([F:29])[F:30])[CH:26]=[CH:27][C:15]=1[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:9]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:37]=2)=[CH:10][CH:11]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(-c2cccc(CC(=O)O)c2)cc1

Procedure:
According to a method similar to Example (8-1), from tert-butyl 2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-5-(trifluoromethyl)benzoate (88 mg, 0.18 mmol) obtained in Example (2-4) and 3-bromophenylacetic acid (50 mg, 0.23 mmol), the title compound was obtained as a yellow powder (4.5 mg, yield: 29%).
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[CH3:10][N:11]([CH3:23])[C:12]1[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=1)[C:17]#[N:18].Cl>O1CCCC1>[CH3:10][N:11]([CH3:23])[C:12]1[CH:13]=[CH:14][C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH:19]=1)[CH2:17][NH2:18]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)c1ccc([N+](=O)[O-])c(CN)c1
Reaction time: 8 h

Procedure:
A solution consisting of 120 ml of trifluoroacetic acid and 200 ml of tetrahydrofuran was added to a solution of 60 g of sodium borohydride in 300 ml of tetrahydrofuran under ice-cooling to a temperature of 15° C. or less. 63.4 of 5-dimethylamino-2-nitrobenzonitrile was added to the mixture, followed by stirring. After cooling the heat generated, the stirring was continued at room temperature overnight. 650 ml of a 10% aqueous solution of hydrochloric acid was then added thereto, followed by heat-refluxing for 1.5 hours. The tetrahydrofuran was removed by distillation under reduced pressure. The aqueous layer was washed with benzene, rendered alkaline with a sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, dried and distilled off to remove the chloroform. The residue was purified by silica gel chromatography to obtain 33.4 g of 5-dimethylamino-2-nitrobenzylamine (melting point: 97°-98° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(O)C.[OH-].[K+]>O>[CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:30])([CH3:32])[CH3:31])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1/C(=C/c1ccc(C(=O)O)cc1)[Si](C)(C)C)C(C)(C)CCC2(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl(Z)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]benzoate (Compound 4, 0.034 g, 0.076 mmol) and 2 mL of ethyl alcohol was added aqueous 1 N KOH (0.5 mL). The resulting solution was heated in an 50° C. bath until the hydrolysis reaction was completed, as judged by thin layer chromatography. The solution was cooled to room temperature, diluted with water and washed once with 1:1 ether:hexane solution, and the layers were separated. The aqueous layer was acidified with 1 N aqueous HCl and the product extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered, and the solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][NH2:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[N+:16](=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[N-:17]
Reactant: NN=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
To a solution of [bis-(4-chloro-phenyl)-methylene]-hydrazine from Step 1 (2.0 g, 7.5 mmol) in CHCl3 (20 mL) was added MnO2 (5.0 g, 57 mmol). The resulting reaction mixture was stirred 1 h at 21° C., then filtered on a bed of MgSO4 and the filtrate concentrated to provided the diazo bis-(4-chloro-phenyl)-methane compound as a purple solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2)[CH3:3].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:6]=1
Reactant: COc1ccc2c(=O)[nH]c(CN(C)C)c(-c3ccccc3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
3-[(dimethylamino)methyl]-6-methoxy-4-phenylisoquinolin-1(2H)-one (50 mg) was combined with 0.600 mL of POCl3, and the reaction was stirred at 90 C for 1 h. After cooling, the reaction was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic solution was dried over Na2SO4 and concentrated. Flash chromatography (3% MeOH in CH2Cl2) gave the titled compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@:20]([OH:45])([CH2:43][OH:44])[C@H:21]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])=[CH:30][CH:29]=2)[C:24]1=[O:42])[CH3:22]>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@:20]([OH:45])([CH2:43][O:44][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:21]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:41])([F:40])[CH:37]([F:38])[F:39])=[CH:30][CH:29]=2)[C:24]1=[O:42])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(CO)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Metanesulfonyl chloride (2.12 g) and triethylamine (1.87 g) were added dropwise to an ice-cooled solution of 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (5.85 g) in ethyl acetate (60 ml). The resulting mixture was stirred for 20 minutes at 0° C. and then washed with water (20 ml×2) and an aqueous sodium chloride solution (20 ml) successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (6.8 g) as a colorless oil. This compound (6.8 g) was dissolved in N,N-dimethylformamide (130 ml). 1H-1,2,4-Triazole (4.24 g) and potassium carbonate (16.9 g) were added to the solution. The resulting mixture was heated at 80° C. for 5 hours, and then concentrated in vacuo. The residue was diluted with ethyl acetate (200 ml) and the mixture was washed with water (40 ml×2), 1N-hydrochloric acid (40 ml×2) and an aqueous sodium chloride solution successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (100 g; eluent, hexane-ethyl acetate, 2:1 to 1:2) followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (4.4 g, 68%) as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH3:38])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a mixture of 4-hydroxy-benzoic acid methyl ester (152 mg, 1 mmol) and potassium carbonate (152 mg, 1.1 mmol) add acetonitrile (4 mL). To this mixture add 5-bromomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (Example 4, 314 mg, 1 mmol). Warm the resulting reaction mixture to 60° C., and stir at this temperature for 5 hrs. Cool the mixture to room temperature, dilute with ethyl acetate, wash with water, then brine, dry over MgSO4, filter and concentrate to give the title compound as a white solid (364 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH:12]([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(N=C(c2ccccc2)C(C)C)c(C)c1
Temperature: 220 °C

Procedure:
2,4,6-Trimethylaniline (16.9 mL, 120 mmol, Aldrich) was mixed with isobutyrophenone (12.0 mL, 80 mmol, Acros) and p-TsOH (1.5 g, 8.0 mmol, Aldrich). The resulting mixture was heated for 10 h at 220° C. in a flask equipped with a Dean-Stark trap. Vacuum distillation afforded two fractions: 1. unreacted starting materials, 40–48° C./40 Pa; 2. product as a yellow oil, 98–108° C./13 Pa (6.2 g, 29.2%). 1H NMR (toluene-d8, 353 K) 7.28–6.78 (m, 4H); 6.62 (s, 2H); 2.96 (septet, 1H; J=6.7 Hz); 2.07 (s, 3H); 1.97 (s, 6H); 1.23 (d, 6H; J=6.7 Hz).
Reaction SMILES: C(OC[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(=O)C.[CH2:17]1COCC1>>[CH2:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:11]1[CH:17]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OCC1(c2cccs2)C=CC=CC1
Reactant: C1CCOC1
Product: c1ccc(Cc2cccs2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 1-(2-thienyl)benzyl acetate in THF (5 ml) was added carefully to dry liquid ammonia (100 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min, and the reaction was quenched by addition of solid ammonium chloride. The residue, after complete evaporation of liquid ammonia, was dissolved in water (50 ml) and was extracted with methylene chloride (2×50 ml). The combined organic layer was dried over MgSO4 and filtered. Removal of the solvent gave crude product, which was purified by column chromatography using hexane as eluent to give 2-benzylthiophene (1.2 g, 68% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl 4-[2-(4-methanesulfonyl-phenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (164 mg, 0.367 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature overnight and was then concentrated in vacuo. To the residue was added saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (125 mg, yield 98%).
Reaction SMILES: Cl.[C:2]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][Cl:23])=[N:20][C:19]([C:24]([OH:26])=[O:25])=[N:18]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27]O>>[CH3:27][O:25][C:24]([C:19]1[N:20]=[C:21]([CH2:22][Cl:23])[N:17]([C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[C:2](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:18]=1)=[O:26]
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 18 h

Procedure:
224 ml of a 6N solution of hydrogen chloride in methanol is added to a solution of 112.2 g (0.299 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid in 1120 ml of methanol, and the whole is refluxed for 21 hours. There is then distilled off 800 ml of methanol at normal pressure, and the concentrated solution is allowed to stand for 18 hours at room temperature. The product that has crystallised out is filtered off under suction and washed with cold methanol and hexane. After drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 132°-134°.