Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](F)[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:30][CH2:29]1.CC(C)([O-])C.[K+]>COCCOCCOC.ClCCl.O>[NH3:8].[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:37][CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCCN1CCC(Oc2cc(F)cc3nc[nH]c(=O)c23)CC1
Reactant: CN1CCN(CCCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOCCOC
Product: CN1CCN(CCCOc2cc(OC3CCN(CCOC(C)(C)C)CC3)c3c(=O)[nH]cnc3c2)CC1
Product: N
Yield: 109.2 %

Procedure:
5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin-4(3H)-one (5.45 mg, 1.5 mmol) in anhydrous diglyme (15 ml) was reacted with 3-(4-methylpiperazin-1-yl)propan-1-ol (474 mg, 3 mmol) in the presence of potassium tert-butoxide (11.77 g, 10 mmol) at 100° C. for 4 hours. The reaction mixture was diluted with dichloromethane (10 ml) and water (10 ml) and the pH adjusted to 7.7. The mixture was extracted several times with dichloromethane and the organic phase dried (magnesium sulphate), evaporated and the residue purified by chromatography on silica gel. Elution with dichloromethane:methanolic ammonia (9:1) yielded 5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4(3H)-one (411 mg, 55% yield):
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br-:1].[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCCCCBr
Product: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 150 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
10-Bromodecanoic acid (19.65 g, 78.24 mmol) and triphenylphosphine (21.45 g, 81.78 mmol) were mixed and stirred at 150° C. for 24 h. Wittig reagent B2 as light yellow syrup was obtained in 100% yield and used without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][CH2:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N+:23]([O-:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N+:16]=1[O-:30].C(OCC)C>C(Cl)(Cl)Cl>[CH3:12][S:13]([CH2:14][C:15]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[N+:23]([O-:29])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N+:16]=1[O-:30])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(CSC)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CS(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1 h

Procedure:
A solution of m-chloroperbenzoic acid (9.4 g., 0.0465 m of 85 percent material) in chloroform (75 ml.) was added dropwise to a solution of 2-methylthiomethyl-3-carbomethoxyquinoxaline 1,4-dioxide (13.0 g. 0.0465 m) in chloroform (100 ml.). The mixture was stirred for one hour and then added dropwise, with stirring, to diethyl ether (1.1 liters). The yellow solid which precipitated was filtered off, washed with diethyl ether (50 ml.) and then with hexane (100 ml.) and dried. Yield = 13.4 g., 97 percent of product: m.p. 141°-142°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1.C(OC(N1CCC(NC(=O)C2C=C(OCCCC(OC)=O)C=C(OC)C=2)CC1)=O)(C)(C)C.[CH2:58]([O:60][C:61]1[CH:62]=[C:63]([CH:66]=[C:67]([O:70][CH2:71][CH3:72])[C:68]=1[F:69])[CH:64]=O)[CH3:59].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:64][C:63]3[CH:66]=[C:67]([O:70][CH2:71][CH3:72])[C:68]([F:69])=[C:61]([O:60][CH2:58][CH3:59])[CH:62]=3)[CH2:20][CH2:21]2)[CH:13]=1
Reactant: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCCCC(=O)OC)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 4-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-butyric acid methyl ester [prepared from 4-[3-methoxy-5-(3-methoxycarbonyl-propoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester by Boc cleavage in analogy to example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 547.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3].Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([S:24][CH2:26][C:27]5[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=5)[C:30]#[N:31])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc32)cc1
Yield: 67 %

Procedure:
In the same manner as in Example 7 and using 5-[1-[4-(methylsulfinyl)phenyl]-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([OH:26])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:35][NH2:36]>>[OH:35][NH:36][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])=[O:26]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Product: O=C(NO)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 46.2 %

Procedure:
A solution of the acid obtained in Example 7 (1.00 g, 2.66 mmol) was reacted with oxalyl chloride (2M solution in CH2Cl2, 6.65 mL, 13.3 mmol) followed by O-(trimethylsilyl)hydroxylamine (2.8 g, 26.64 mmol) as described in Example 2 to obtain 0.48 g (46%) of the desired product. The melting point was 182-184° C. Mass spectrometry revealed a molecular ion (MH)+ peak at m/z 391. Proton NMR analysis in CDCl3 resulted in the following chemical shifts (δ): 0.98-1.96 (m, 8H, cyclohexyl methylenes), 2.05-2.16 (m, 1H, C-1H), 3.50-3.67 (broad hump, 1H, C-2H), 6.15 (broad hump, 1H, SO2NH), 7.01-7.88 (m, 9H, aryl-H), and 8.98 (broad s, 1H, CONH).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:60])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:57]=[CH:58][CH:59]=1)[C:19]([NH:21][C:22]1[C:23]([CH3:56])=[C:24]([C:31]([C:33]2[CH:34]=[CH:35][C:36]([NH:49][C:50](=[O:55])[C:51]([F:54])([F:53])[F:52])=[C:37]([CH:48]=2)[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[O:32])[N:25]2[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]2)=[O:20])(C)(C)C.C(OCC)C>ClCCl>[CH2:41]([O:40][C:38]([C:37]1[CH:48]=[C:33]([CH:34]=[CH:35][C:36]=1[NH:49][C:50](=[O:55])[C:51]([F:54])([F:53])[F:52])[C:31]([C:24]1[N:25]2[C:30]([CH:29]=[CH:28][CH:27]=[CH:26]2)=[C:22]([NH:21][C:19]([C:18]2[CH:17]=[C:16]([CH:59]=[CH:58][CH:57]=2)[O:15][CH2:14][C:13]([OH:60])=[O:12])=[O:20])[C:23]=1[CH3:56])=[O:32])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Cc1c(NC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)c2cccc(OCC(=O)O)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Yield: 98.7 %

Procedure:
17 ml (0.22 mol) of trifluoroacetic acid are added to the suspension of 7.95 g (10.9 mmol) of benzyl 5-[(1-{[3-(2-tert-butoxy-2-oxoethoxy)benzoyl]amino}-2-methylindolizin-3-yl)carbonyl]-2-[(trifluoroacetyl)amino]benzoate in 55 ml of dichloromethane at ambient temperature. The mixture becomes rapidly homogenized. The solution is stirred for 3 hours and concentrated to dryness. The solid obtained is taken up with ethyl ether, filtered and dried. 7.25 g (99%) of an orange powder are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].B(F)(F)F.[CH3:61][CH2:62][O:63][CH2:64]C.[N+](=C[C:69]([O:71]CC)=[O:70])=[N-]>C(OCC)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([C:69]([O:71][CH2:64][O:63][CH2:62][CH3:61])=[O:70])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CCOCC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Product: CCOCOC(=O)C1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CC1OC
Reaction time: 12 h
Yield: 38.5 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg., 0.253 mmol., 1 eq.) in diethyl ether (6 mL.) was added boron trifluoride etherate (0.009 mL., 0.073 mmol., 0.3 eq.) and ethyl diazoacetate (0.080 mL., 0.760 mmol., 3 eq.). The reaction mixture was stirred 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The products were isolated by preparative TLC on silica gel (3:2 EtOAc/hexanes) and a second preparative TLC (eluted 2× with 3:1 hexanes/acetone) affording 24.7 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(ethoxycarbomethoxy)-3 "-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR, 13C NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CN1CC[O:19][CH2:18][CH2:17]1.C(Cl)(=O)C>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[C:6]([NH:7][C:18](=[O:19])[CH3:17])[CH:8]=1
Reactant: CCCS(=O)(=O)c1ccc(C)cc1N
Reactant: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCCS(=O)(=O)c1ccc(C)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A solution of 5-methyl-2-(propylsulfonyl) aniline (Intermediate 228; 6.0 g, 28 mmol) in DCM (100 ml) was added N-methyl morpholine (4.3 g, 42.1 mmol) and Acetyl chloride (2.4 g, 31 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (200 ml), the organic layer was washed with brine solution and dried over sodium sulphate and evaporated. The crude product was purified by column chromatography (silica) using petroleum ether/ethyl acetate as eluent to afford the title compound (5.0 g, 70%) as a white solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>C1COCC1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[C:24]([O:26][C:35]1[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=1[F:29])=[O:25]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cccc(C(F)(F)F)c1
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (1.1 g, 5.3 mol) was added to a solution of α,α,α-trifluoro-m-toluic acid (1.0 g, 5.3 mmol) and pentafluorophenol (1.1 g, 5.8 mmol) in THF (10.0 mL). After stirring for 3.5 h, the solvent was removed under vacuum. The residue was dissolved in Et2O (20 mL), filtered, and washed with brine (2×10 mL), dried over Na2SO4, filtered, and evaporated to dryness to provide compound perfluorophenyl 3-(trifluoromethyl)benzoate as a yellow oil (1.7 g, 90%): 1H NMR (300 MHz, CD3OD) δ 8.51-8.39 (m, 2H), 8.09 (d, J=6.0 Hz, 1H), 7.88-7.79 (m, 1H); 19F NMR (282 MHz, CD3OD) δ −64.9 (3F), −155.6 (2F), −165.7 (1F), −168.9 (2F).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>C(Cl)Cl>[Br:52][CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:15]1[CH:25]=[CH:26][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:31])([F:30])[F:1])=[CH:13][C:14]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CBr)c1
Yield: 84.1 %

Procedure:
A solution of (3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)phenyl) methanol (1.09 g, 2.40 mmol) in methylene chloride (24 mL) was added with triphenylphosphine (0.95 g) and carbon tetrabromide (1.27 g) at 0° C. After completion of the reaction, the reaction solution was concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (1.04 g, yield 85%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=2)[C:13]#N)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH2:26].[OH-:27].[Na+].Cl>C(O)C.CC(OC)(C)C>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=2)[C:13]([OH:27])=[O:26])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [OH-]
Reactant: O
Reactant: COCC(C)Oc1cc(C#N)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
3-(4-Methanesulfonyl-phenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzonitrile (0.1 g, 0.27 mmol) was dissolved in ethanol (1.0 ml) and charged to a 5 ml round bottomed flask equipped with a condenser. Water (0.2 ml, 11.1 mmol) was added, followed by sodium hydroxide (18.9M in water, 0.2 ml, 3.78 mmol). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated in vacuo, the residue was partitioned between water (10 ml) and MTBE (10 ml) and the layers were separated. The aqueous phase was acidified to pH 1 with 2M HCl (2.5 ml, 5 mmol) and MTBE (10 ml) was added to extract the product. This MTBE extract was dried over MgSO4, and then evaporated in vacuo to give the title product as a white solid (0.1 g, 100% yield).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[CH3:35][S:36]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 84.0 g of N-triphenylmethyl-4-piperidinemethanol and 36.2 ml of triethylamine in 420 ml of dried tetrahydrofuran, 18.3 ml of methanesulfonyl chloride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was added with waiter and extracted with diethyl ether. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting residue was added with a mixture of isopropanol and methanol, and the precipitated crystals were collected by filtration and washed with methanol to give 90.4 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless prisms having the melting point of from 129.5 to 134° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=C=Nc1ncc(Br)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (13.5 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was then stirred at room temperature for a period of about one hour. After this time the reaction mixture was filtered, and the filtrate was stripped of solvent under reduced pressure, leaving an oil. This oil was chromatographed on silica gel using ethyl acetate as the diluant. The eluant was dissolved in an ethanol-water mixture, and the solution was filtered. The filtrate was then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-bromothiazol-2-yl)ureido]acetaldehyde as a crystalline solid having a melt point of 72° to 73° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].C([CH:25]([NH2:28])[CH2:26]C)C.CN1CC[CH2:32][C:31]1=[O:35]>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N:28]([CH2:25][CH3:26])[CH2:32][CH2:31][OH:35])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CN1CCCC1=O
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Product: CCN(CCO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in 1-methyl-2-pyrrolidinone was heated at 130° C. until starting material was consumed. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 6.85(s,2H), 6.40(s,1H), 3.88(s,3H), 3.73(t,2H), 3.43(t,2H), 3.31(q,2H), 2.27(s,3H), 2.22(s,3H), 2.06(s,6H), 1.15(t,3H) ppm.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C-:7]#[N:8].[K+].CO.C1COCC1.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]([N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])[C:7]#[N:8])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCNCC
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CCN(CC)C(C#N)c1ccc(OCc2ccccc2)cc1
Yield: 589 %

Procedure:
Diethylamine hydrochloride (76.7 g, 70 mmol) was added portion wise at rt to a 200 mL aqueous solution of potassium cyanide (45.5 g, 70 mmol) with stirring and warmed to 60°-65° C. A MeOH/THF (300 ml, 1:1) solution of 4-(benzyloxy)-benzaldehyde (100 g, 47 mmol) (Aldrich) was added in a thin stream to the aqueous solution and stirred for 16 hr at ~62° C. The reaction mixture was allowed to cool and the organics were removed in vacuo. The aqueous portion was diluted with an equal volume of brine and extracted several times with EtOAc. The EtOAc extracts were combined, washed with H2O, dried (Na2SO4), and concentrated to a tacky amber solid. The material was triturated with petroleum ether and filtered to give a yellow solid, which was taken up in warm Et2O, charcoaled, filtered, diluted with petroleum ether, and allowed to crystallize. The crystals were filtered and dried in vacuo to give 81.5 g (59%) of the desired product: mp 75°-76° C.; 1H NMR (CDCl3) d 1.06-1.11 (t, 6H, J=7 Hz, CH3), 2.42-2.49 (m, 2H, NCH2), 2.66-2.73 (m, 2H, NCH2), 4.98 (s, 1H, CHCN), 5.09 (s, 2H, OCH2), 6.99-7.01 (d, 2H, J=7 Hz, ArH), 7.35-7.49 (m, 7H,ArH); MS(FD) 294(M+). Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.51. Found: C, 77.70; H, 7.64; N, 9.45.
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=CC(C(O)=O)=C[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.C1(N=C=NC2CCCCC2)CCCCC1.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[CH2:2]1[C:3]2[C:17](=[CH:18][C:19]([C:20]([NH2:16])=[O:21])=[CH:5][CH:4]=2)[CH2:9][CH2:10][C:1]1=[O:14]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was codissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0C and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Ammonium chloride (333 mg, 6.23 mmol) and triethylamine (1.58 mL, 12.5 mmol, d=0.797) were added. The solution was stirred at ambient temperature for 16 hours. The suspended urea and salts were filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of 2-tetralone-6-carboxamide, ethylene ketal as a white solid, clean by NMR, TLC.