Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Cl[C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[N:17]1[C:18]2[NH:1][C:2]3[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][C:3]=3[S:12][C:19]=2[N:20]=[CH:21][CH:16]=1
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)c1cnc(S)c(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2c(c1)Nc1nccnc1S2
Yield: 30.4 %

Procedure:
To a solution of 1.0 g of methyl 5-amino-6-mercaptonicotinate in N,N-dimethylformamide (30 ml) were added 0.52 g of sodium hydride (oily: 60% or more) and 0.97 g of 2,3-dichloropyrazine and the resulting mixture was reacted at 100° C. for 2 hours. Then ethyl acetate was added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 0.43 g of crude methyl 10H-pyrazino[2,3-b]pyrido[3,2-e][1,4]thiazin-8-carboxylate as a brown solid. To a solution of 1.43 g of these crude crystals in N,N-dimethylformamide (50 ml) were added 0.26 g of sodium hydride (60% oily) and 0.5 g of chloromethyl methyl ether and the resulting mixture was reacted under ice-cooling for 1 hour. After adding ethyl acetate, the mixture was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, diethyl ether was added to the residue and the crystals thus precipitated were taken up by filtration to thereby give 1.5 g of the title compound as red crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)cc1
Yield: 24.2 %

Procedure:
Compound 42 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([C@@H:19]([NH2:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 106.4 %

Procedure:
To a solution of the above tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate 50a (40 mg, 0.096 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 52 (32.7 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8.0 Hz, 1 H), 7.27 (d, J=2.0 Hz, 1 H), 7.15 (m, 2 H), 7.02 (m, 2 H), 6.72 (d, J=7.6 Hz, 1 H), 4.04 (dd, J=5.2, 12.0 Hz, 1 H), 2.95 (m, 2 H), 2.78 (dd, J=12.0, 15.6 Hz, 1 H), 2.13 (m, 1 H), 1.80 (m, 1 H), 1.51 (q, J=12.4 Hz, 1 H), 1.35 (broad, 1 H), 1.14 (d, J=6.4 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 147.67, 138.79, 137.29, 132.64, 130.88, 130.68, 130.41, 129.57, 129.43, 128.43, 126.58, 126.15, 51.16, 46.91, 42.31, 37.48, 32.60, 21.20; ESI MS m/z 320.1.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=NN=2)=[CH:16][CH:15]=1.C([O-])([O-])=[O:26].[Cs+].[Cs+].CI>C1COCC1>[CH3:7][N:6]1[CH:2]=[C:3]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:21][CH3:22])=[O:26])=[CH:16][CH:15]=2)[N:4]=[C:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nnco3)cc2)c1I
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methyl 4-(2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (from Step 1, 19.55 g, 70 mmol) was dissolve in THF (160 mL), to which was added Cs2CO3 (29.6 g, 91 mmol) at 0° C. After stirring for 5 min, MeI (11 mL, 175 mmol) was added. After stirring overnight at rt, the reaction was quenched with aq NH4Cl. The product was extracted with EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-20% EtOAc in hexanes) to give 12.5 g of methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. LCMS: m/z 294 (M+H)+.
Reaction SMILES: [K].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH2:25].Cl>O1CCCC1>[OH:25][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
In a reaction container equipped with a stirring device, a thermometer and a tap funnel, 14.8 g of potassium tert-buthoxide and 50 ml of tetrahydrofuran are placed. In nitrogen air stream, a solution in which 9.90 g of 2-hydroxy benzyl diethyl phosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde are dissolved in tetrahydrofuran is slowly dropped to the reaction container at room temperature and the reaction is conducted for 2 hours. Next, while cooling down by water, water is added to the resultant and thereafter 2N hydrochloric acid is added to acidify the resultant. Furthermore, tetrahydrofuran is removed by an evaporator and the obtained coarse product is extracted by toluene. The toluene phase is washed with water, sodium hydrogen carbonate aqueous solution and saturated salt solution in this order. After magnesium sulfide is added, the resultant is dehydrated. Subsequent to filtration, toluene is removed and an oily coarse product is obtained. Subsequent to column refinement by silica gel, the resultant is crystallized in hexane and 5.09 g (yield ratio: 72%) of 2-hydroxy-4′-(N,N-bis(4-methylphenyl)amino)stilbene is obtained. The melting point of the product is 136.0 to 138.0° C.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17]([OH:19])=[O:18])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)CCC.C1(C)C=CC=CC=1>[CH:13]1[C:10]2[CH2:11][C:12]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][CH:7]([C:17]([O:19][CH2:12][CH2:1][CH2:2][CH3:3])=[O:18])[O:8][C:9]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1Oc2ccccc2Cc2ccccc2O1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)C1Oc2ccccc2Cc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 500 ml round bottom flask fitted with a stir bar and a Dean-Stark apparatus is placed 111.4 grams of crude (87 percent) 12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid in 300 ml of 2:1 n-butanol:toluene. The mixture is stirred at room temperature for 15 minutes to effect the complete dissolution of the acid. Concentrated sulfuric acid (4.0 ml) is then added and the reaction mixture is heated to reflux Immediately upon attaining reflux, an aqueous layer begins to separate out in the Dean-Stark apparatus. After 2 hours at reflux, no additional water formation is observed and the reaction is cooled to room temperature with a cold water bath. A total of 10 ml of water is collected, the majority of this water being formed in the initial 30 minutes of reflux. The cooled reddish-yellow reaction solution is diluted with 200 ml of toluene, washed with 300 ml of water, 300 ml of saturated aqueous NaHCO3, ml of brine and then concentrated under reduced pressure on a rota-vap. Toluene (200 ml) is added to the residue and the solution again is concentrated under reduced pressure This evaporation with toluene facilitates the removal of n-butanol. The residue obtained is taken up into 300 ml of 2:1 toluene:ether and washed with 200 ml of 5 percent NaOH. Brine, 50 ml, is added to break up the emulsion that forms with the 5 percent NaOH wash. The organic solution is then washed with 200 ml of brine, dried over MgSO4 and concentrated under reduced pressure to afford a thick light reddish-yellow liquid (130 grams). This liquid is then subjected to vacuum distillation, using a Claisen adapter as the distillation head and an oil bath for heating. Care is taken during the course of the distillation to avoid solidification of the product in the distillation condenser. A forerun (11 grams) is collected having a b.p. 70° C. to 170° C. at 0.25 mm. Pure n-butyl ester, 84.3 grams (62 percent), is then collected from 171° C. to 180° C. at 0.25 mm as a thick clear liquid which readily solidifies on cooling to afford a white solid: mp 63°-66° C. (softening at 60° C.); greater than 99 percent purity as determined by L.C. bp 189°-195° C./0.4mm; IR (neat) 3.45, 5.75, 6.95, 8.35, 10.4 cm-1 ; H NRM (60 MHz, CDCl3) δ 0.9-1.9 (m, 7, OCH2CH2CH2CH3), 3.42 and 4.6 (2d, 2, CH2), 4.35, (t, 2, OCH2CH2CH2CH 3), 5.05 (s, 1, CH), 7.0-7.4 (m, 8, Ar--H)).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([NH2:27])=[S:26])[CH:21]=[N:20][CH:19]=1.CC1N=C(NC2C=NC=CN=2)SC=1C1C=CC(S(N)(=O)=O)=CC=1>>[CH3:16][O:17][C:18]1[N:23]=[C:22]([NH:24][C:25]2[S:26][C:12]([C:9]3[CH:10]=[CH:11][C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=3)=[C:13]([CH3:14])[N:27]=2)[CH:21]=[N:20][CH:19]=1
Reactant: CNS(=O)(=O)c1ccc(CC(C)=O)cc1
Reactant: COc1cncc(NC(N)=S)n1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Product: CNS(=O)(=O)c1ccc(-c2sc(Nc3cncc(OC)n3)nc2C)cc1

Procedure:
Using N-methyl-4-(2-oxo-propyl)-benzenesulfonamide (18a) and (6-methoxy-pyrazin-2-yl)-thiourea in an identical process to that described for the preparation of 4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (Example 1) afforded the title compound.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH2:3]1.CCN(C(C)C)C(C)C.[N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]2=[C:34]([C:41](Cl)=[O:42])[CH:33]=1>C1COCC1>[F:22][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH:21][C:41]([C:34]2[CH:33]=[N:32][N:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=23)=[O:42])[CH2:3]1
Reactant: C[Si](C)(C)COCCn1ncc(N)c1N1CCCC(F)(F)C1
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (1.2 g, 3.61 mmol) in 30 mL THF was added DIPEA (1.3 mL, 7.22 mmol) and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (720 mg, 3.97 mmol) in THF (50 mL) at 0° C. After addition was complete, the mixture was warmed to room temperature, then stirred overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatogaphy (hexanes:EtOAc=3:1 to 1:1) to afford 1.0 g (60%) of N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=478.2; 1H NMR (400 MHz, CDCl3) δ: 9.49 (s, 1H), 8.87 (dd, 1H), 8.75 (s, 1H), 8.71 (dd, 1H), 7.94 (s, 1H), 7.10 (dd, 1H), 5.40 (s, 2H), 3.67 (m, 6H), 2.06 (s, 2H), 1.93 (m, 2H), 0.95 (m, 2H), 0 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:28][CH3:29])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CCI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) in 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) of cesium carbonate followed by 0.8 mL (0.0099 mole) of iodoethane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 0.90 g of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(Cc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C(Cc1ccc(C#N)cc1)C1CCCN1

Procedure:
(R)-1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl-acetic acid methyl ester (0.5 g, 2.06 mmol) is treated with lithium bis(trimethylsilyl)amide and 4-bromomethylbenzonitrile (1.0 g, 5.14 mmol) as described in EXAMPLE 1B to give 3-(4-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester as a mixture of stereoisomers. This material is coupled with biphenyl-4-carboxylic acid to give 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-3-(4-cyanophenyl)-propionic acid methyl ester (0.5 g, 1.1 mmol). This material is converted to the title compound (0.47 g, 0.83 mmol) by the procedure described in EXAMPLE 1C. 1H NMR (DMSO-d6, 300 MHz) □ 9.35-9.11(m,4H), 7.78-7.32 (m, 13H), 4.52, 4.36(two m, 1H), 3.58, 3.51 (two s, 3H), 3.50-3.25(m,3H), 3.14-2.95(m, 1H), 2.95-2.80(m, 1H), 2.20-1.55(m, 4H). MS m/z: [M+H]+=456
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:50](Cl)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[C:50]([O:23][CH:22]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In 200 ml of dried dichloromethane was dissolved 32.0 g (53.4 mmole) of 1-trityl-3-octadecylglycerol, and 22.4 ml of dried pyridine and then a solution of 6.7 ml (57.9 mmole) of benzoyl chloride in 100 ml of dried dichloromethane were added dropwise to the solution under stirring at 0° to 3° C. over the period of time of 30 minutes. The reaction mixture was stirred at room temperature for another 2 hours, and then concentrated under reduced pressure. 200 ml of ether was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 28.8 g (7%) of 2-benzoyl-3-octadecyl-1-tritylglycerol as an oily material.
Reaction SMILES: F[C:2]1[C:9]([Si](C)(C)C)=[C:8]([I:14])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][SH:20])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]([C:19]1[S:20][C:2]2[CH:9]=[C:8]([I:14])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:21])[CH3:16]
Reactant: C[Si](C)(C)c1c(I)ccc(C=O)c1F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(I)cc2s1
Temperature: 75 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 2-fluoro-4-iodo-3-trimethylsilanyl-benzaldehyde (14.2 g, 44.1 mmol) (Tetrahedron Letters 1992, p 7499-7502) in DMF (50 mL) is treated with mercapto-acetic acid ethyl ester (5.80 mL, 52.9 mmol) and K2CO3 (12.2 g, 88.2 mmol). The resulting suspension is stirred at 75° C. for 60 min and quenched with water (300 mL). The mixture is extracted with EtOAc (3×50 mL,) and the organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (5-20% EtOAc/Hex), to give the title compound as an oil (9.40 g, 64%).
Reaction SMILES: CO.[C:3]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)(=O)[CH2:4][CH2:5][CH3:6].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>Cl>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[CH:29][C:30]([NH:33][CH:3]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=3)[CH2:4][CH2:5][CH3:6])=[CH:31][N:32]=2)=[CH:25][CH:26]=1
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Methanol (0.70 mL) was added to a flask containing ethyl 4-butyrylbenzoate (82.8 mg, 0.376 mmol), 2-(4-(trifluoromethyl)phenyl)pyrimidin-5-amine (90.0 mg, 0.376 mmol) and decaborane (46.0 mg, 0.376 mmol) at room temperature under nitrogen. The resulting solution was stirred at room temperature overnight. The mixture was diluted with 1N HCl and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) gave ethyl 4-(1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-ylamino)butyl)benzoate (40.0 mg, 24%). 1H NMR (400 MHz, CDCl3, δ): 8.32 (d, J=8.19 Hz, 2 H), 8.07 (s, 2 H), 7.98-8.04 (m, 2 H), 7.63 (d, J=8.19 Hz, 2 H), 7.36-7.41 (m, 2 H), 4.38-4.43 (m, 2 H), 4.35 (q, J=7.02 Hz, 2 H), 1.75-1.91 (m, 2 H), 1.36 (t, J=7.02 Hz, 3 H), 1.20-1.52 (m, 2 H), 0.94 (t, J=7.32 Hz, 2 H). MS (M+1): 444.3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:21]3[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (1.4 g, 5.71 mmol) in dimethylformamide (10 mL) at room temperature was added sodium hydride slowly (0.5 g, 60%, 12.4 mmol). After effervescence subsided, tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate (1.03 g, 4.75 mmol) was added slowly. The mixture was stirred at room temperature overnight and then poured into ice-water. The residue was purified by flash chromatography (silica gel, 2% methanol in methylene chloride) to afford the title compound as a yellow solid (2.75 g, 99%). 1H-NMR (CDCl3, 300 MHz): δ 8.64 (s, 1H), 7.97 (dd, 1H), 7.47 (d, 2H), 6.98 (d, 2H), 6.79 (d, 1H), 5.37 (m, 1H), 4.91 (d, 1H), 3.93 (m, 2H), 3.63 (m, 2H), 3.29 (m, 2H), 2.861 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.43 (s, 9H), 1.41 (m, 2H); LCMS: MS (m/z): 585 (MH+)