Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:8]>C(O)C.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH2:24])=[O:23])=[O:19])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:8]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1CCCCC1)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC1CCCCC1)NC(=O)[C@@H]1CCC(=O)N1
Yield: 94.7 %

Procedure:
3.07 g (6 mmoles) of Z-Glp-Cha-Pro-NH2 are dissolved in 60 ml of ethanol, 0.6 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 2 hours. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. 2.15 g (95%) of Glp-Cha-Pro-NH2 are obtained as an amorphous solid; Rf4 =0.50, [α]D25 =-70.9° (c=1%, in acetic acid).
Reaction SMILES: C1C[O:4][CH2:3]C1.[NH2:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([F:17])[C:8]=1[C:9]([OH:11])=[O:10].CCN(C(C)C)C(C)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.C(#N)C>[F:17][C:12]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]2[NH:6][C:3](=[O:4])[O:16][C:15]2=[CH:14][CH:13]=1
Reactant: Nc1c(O)ccc(F)c1C(=O)O
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)c1c(F)ccc2oc(=O)[nH]c12

Procedure:
To a THF solution of 2-amino-6-fluoro-3-hydroxybenzoic acid (520 mg, 3.04 mmole) and n,n-diisopropylethylamine (942 mg, 7.29 mmole) was added bis(trichloromethyl) carbonate (1.08 g, 3.64 mmole) and stirred. Removal of solvent under vacuum afforded a residue, which was run on reversephase flash chromatography 10 to 90% acetonitrile water (0.01% TFA). The resulting fractions were evaporated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M154) (260 mg, 0.506 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (166 mg, 83%).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][C:22](=[O:33])[N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3C2CCCCO2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:40]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][C:22](=[O:33])[N:23]([CH3:32])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CN(CCc1ccccn1)C(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Product: CN(CCc1ccccn1)C(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aqueous hydrochloric acid (2M, 5 ml) was added to a solution of N′-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea (Preparation 25) in methanol (50 ml). The solution was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and then dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give the title compound (0.161 g) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].Cl.CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (240 mg, 0.48 mmol) was dissolved in THF (3.2 mL) and treated with 4M HCl (1.6 mL, 0.8 mmol). The reaction mixture was heated to 45° C. and stirred at ambient temperature. After 2 h, methanol was added (15-20 drops) and the solution was stirred for 3 h. An additional portion of 4M HCl (1.6 mL, 0.8 mmol) and methanol (1 mL) were added and the solution was stirred 16 h at ambient temperature followed by 40° C. for 4 h. The solution was partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate (sat. aq.) and brine, dried over sodium sulfate and concentrated to 233 mg (quantitative yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.O>CN(C=O)C>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxy thiophenol (5 mL, 40.7 mmol) and methyl-3-nitro-4-chlorobenzoate (10.52 g, 48.8 mmol) in DMF (40 mL) was added CsCO3 (26.5 g, 81.4 mmol) and the reaction mixture heated at 80° C. for 3 hours. After cooling, the solution was poured into water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound after chromatography on silica gel using ethyl acetate/hexanes as eluent (10.93 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:14](=[O:16])[NH:13][CH:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]=3[CH:23]=2)=[C:5]([CH3:24])[O:4][N:3]=1.[H-].[Na+].Br[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:14](=[O:16])[N:13]([CH2:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]=3[CH:23]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: BrCC1CCOCC1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)NC(=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(CC1CCOCC1)C(=O)O2
Temperature: 25 °C

Procedure:
6-(3,5-Dimethyl-isoxazol-4-yl)-4-phenyl-3,4-dihydro-benzo[e][1,3]oxazin-2-one (20 mg, 0.06 mmol) is dissolved in DMF 0.5 mL. Sodium hydride (60% w/w, 2.6 mg, 0.065 mmol) is added. The mixture is cooled in an ice bath. 4-bromomethyltetrahydropyran (14 mg, 0.074 mmol) is added and the mixture stirred and allowed to warm to room temperature over night. Sodium hydride (0.5 mg, 0.013 mmol) is added and the mixture stirred at room temperature for a further 3 hours. The mixture is quenched by the addition of water (1 mL). The solvent is removed in vacuo and the residue is purified by preparative HPLC. The product fraction is lyophilized to produce the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=O)=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].[CH3:24][NH:25][CH3:26]>C(O)C>[CH3:24][N:25]([CH2:21][C:19]1[S:20][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:6]=[C:7]([CH3:10])[C:8]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[N:12][N:13]=2)=[CH:17][C:18]=1[CH3:23])[CH3:26]
Reactant: CNC
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1O
Solvent: CCO
Product: CCc1cc(-c2nnc(-c3cc(C)c(CN(C)C)s3)s2)cc(C)c1O

Procedure:
The title compound (13 mg) is prepared staring from 5-[5-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-thiophene-2-carbaldehyde (21 mg, 61 μmol) and dimethylamine (33 mg, 244 μmol, as a 33% solution in ethanol) according to Method C; LC-MS: tR=0.56 min; [M+1]+=374.07; 1H NMR (D6-DMSO): δ1.18 (t, J=7.3 Hz, 3H), 2.20 (s, 3H), 2.24 (s, 6H), 2.26 (s, 3H), 2.67 (q, J=7.3 Hz, 2H), 3.57 (s, 2H), 7.47 (s, 1H), 7.56 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[BH4-].[OH-:31].[Na+].OO.[Na+].[Cl-]>C(OCC)(=O)C.C(COC)OC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:16][CH2:17][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:19][C@H:20]2[OH:31])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C[C@H](c1ccccc1)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Agent: OO
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Temperature: 0 °C
Reaction time: 2.75 h

Procedure:
The reaction flask was charged under argon with 60 g (162 mmol) of (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-1,2,3,6-tetrahydro-pyridine and 600 mL of dimethoxyethane. After addition of 9.2 g (243 mmol) of sodium-borohydride the mixture was cooled to 0° C. under stirring. Then 45.9 g (323 mmol) of borontrifluoride-diethyletherate was added during 40 min, wherein the temperature was kept at 0-5° C. The reaction mixture was stirred at 5° C. for additional 2 h and then at room temperature for 165 min. After cooling to 0° C., 350 mL of 4 N NaOH was added during 1 h, wherein the temperature was kept at 5-10° C. Then 60 mL of 30% H2O2 was added at 20° C. during 1 h. After additional stirring for 20 min the mixture was heated to 45° C., which caused the temperature to raise temporarily to 55° C. After cooling, the temperature was kept at 45° C. for a total of 3 h. After stirring overnight at room temperature the reaction mixture was poured into a mixture of 1 L half-saturated NaCl solution and 800 mL of ethyl acetate. After extraction with ethyl acetate the organic phases were washed with water and dried over Na2SO4. After concentration, 67.4 g of the diastereomeric mixture of (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol and (3S,4S)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol were obtained in a ratio of 3:1.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([P:6]([C:13](=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:5].[CH2:30](O)[C:31]#C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[CH3:22][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]([P:6]([CH2:8][C:9]([O:11][CH2:12][C:30]#[CH:31])=[O:10])([C:4](=[O:5])[C:3]1[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:2]=1[CH3:1])=[O:7])=[O:23]
Reactant: COC(=O)CP(=O)(C(=O)c1c(C)cc(C)cc1C)C(=O)c1c(C)cc(C)cc1C
Reactant: C#CCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C#CCOC(=O)CP(=O)(C(=O)c1c(C)cc(C)cc1C)C(=O)c1c(C)cc(C)cc1C
Yield: 55 %

Procedure:
2.9 g (7 mmol) methyl 2-(bis(2,4,6-trimethylbenzoyl)-phosphinyl)acetate (example 22) is dissolved in a tenfold excess of 2-propyn-1-ol and heated to 90° C. during 12 hours in the presence of 10 mol % dibutyltin dilaurate. Excess 2-propyn-1-ol is distilled off under vacuum and the residual oil purified by preparative column chromatography (silica gel, eluent toluene/ethyl acetate 9:1). 1.7 g (55%) propyn-3-yl 2-[bis(2,4,6-trimethylbenzoyl)-phosphoryl]acetate are obtained as yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[C:19](C)[C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1SC(C)=CC=1.C([N-]C(C)C)(C)C.[Li+].CON(C)C(C1CCN(C(OC(C)(C)C)=O)CC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][C:18]([CH3:24])=[CH:19][C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(Br)s1
Reactant: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Agent: CC(C)[N-]C(C)C
Agent: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Product: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1

Procedure:
Prepared essentially as in 29a except that 2-bromo-5-methyl thiophene is used as the starting material. In addition, 1.20 equivalents of lithium diisopropylamide and 1.24 equivalents of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid. tert-butyl ester are used for the reaction. Accordingly, stirring time of the reaction mixture may vary. Purification of the residue via flash column chromatography uses a gradient with a mixture of ethyl acetate: n-heptane (1:9) to ethyl acetate: n-heptane (2:8) to yield a yellow oil. LC/MS (ESI), m/e 332 (M-56) and 388 (MH+), retention time 2.15 minutes. Condition II.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(OCC)(=O)C>C1COCC1>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C#N)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.46 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at rt for several minutes and then heated to reflux for 15 min. After cooling to rt 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at rt over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. The solvent was removed and the crude product was used as such for Step 2.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=1.[C:10]1([S-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+].CC(C)=O.[OH-].[Na+]>O>[C:10]1([S:16][C:2]2[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [S-]c1ccccc1
Reactant: CC(=O)c1cnc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cnc(Sc2ccccc2)s1
Reaction time: 3 h

Procedure:
1-(2-Chloro-thiazol-5-yl)-ethanone (221 mg, 1.37 mmol) and sodium benzenethiolate (226 mg, 1.71 mmol) were added to acetone (20 mL) and stirred for 3 h. The suspension was poured into water (100 mL) containing 2 M aqueous NaOH (10 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the product. Yield=314 mg, 97%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:21]O)[CH:7]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:9]=1)[CH3:2].S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:21][C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(CO)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Product: CCOc1cc(CCl)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3-Ethoxy-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methanol from Step 2 (350 mg, 1.12 mmol), in dichloromethane (3 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (0.122 mL, 1.68 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. The mixture was evaporated in vacuo to afford the desired product as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:30](=[O:31])[CH:29]=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[C:25]([F:37])([F:38])[F:24])=[CH:15][CH:16]=1
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C(F)(F)F
Yield: 98.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-trifluoromethylcinnamic acid (2.6 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (4.1 g, 99%) as an amorphous solid product.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(CCCCCCC1CCCCC1)CCCCCOC1CCCCO1
Solvent: CO
Product: OCCCCCCCCCCCCC1CCCCC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Into 250 ml of tetrahydrofuran (THF) is dissolved 57.8 g of 2-[(12-bromododecyl)oxy]tetrahydro-2H-pyran, to which a solution of 0.35 g of dilithium tetrachlorocuprate in 16 ml of THF is added dropwise at room temperature with stirring under nitrogen streams. To the resulting solution, a solution of 39.6 g of cyclohexylmagnesium bromide in 200 ml of THF is added dropwise while maintaining the reaction temperature at 10°-15° C. Thereafter, the reaction mixture is stirred for 7 hours at room temperature to complete the reaction. The reaction mixture is then acidified with 2N sulfuric acid under ice cooling. The undissolved substances are removed by filtration and the precipitates are washed with ethyl acetate. The THF layer and the ethyl acetate layer are combined and the resulting solution is washed with water, an aqueous sodium bicarbonate solution and then water and is dried. The solvent is removed by distillation under reduced pressure to leave crude [(12-cyclohexyldodecyl)oxy]-tetrahydro-2H-pyran which in turn is dissolved in 450 ml of methanol. Amberlyst® H-15 (4.5 g) is added to the methanol solution and the mixture is stirred at 45° C. for 2 hours. The resin is then filtered off and the filtrate is concentrated to leave a residue. Purification of the residue by silica gel column chromatography yields 20.6 g of the captioned compound as colorless solids.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([OH:12])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.ClCCl.[CH2:21]=[C:22]([CH3:24])[CH3:23]>O>[C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12][C:22]([CH3:24])([CH3:23])[CH3:21])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C(C)C
Reactant: N#Cc1cccc(CC(O)=S)n1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=S)Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
(6-Cyano-2-pyridyl)thioacetic acid (4.56 g, 23.5 mmol) and concentrated sulfuric acid (1 ml) were added to dichloromethane (300 ml), and isobutene was added thereto. The reaction mixture was sealed and stirred at room temperature for 18 hrs. Water was added to the reaction mixture. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (5.77 g, 98%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1)=[O:23]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccccc4Cl)CC3)cccc2n1
Yield: 45 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-chlorobenzoyl chloride (71.8 mg; 0.41 mmol) to obtain 34.1 mg. (45% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.50 (m, 3H), 7.41 (m, 2H), 7.15 (br s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.92 (br s, 2H), 4.57 (br s, 1H), 3.45 (m, 2H), 3.02 (m, 3H), 2.78 (m, 2H). ESIMS+384.3 m/z
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=O)[CH3:2].C[O:12][CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:10][C:5]1[N:6]=[C:7]([CH3:9])[S:8][C:4]=1/[CH:1]=[CH:2]/[C:13]([N:14]([CH3:16])[CH3:15])=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(C)nc1C
Product: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of 5-acetyl-2,4-dimethylthiazole (10 g, 60 mmol) in N,N-dimethylformamide dimethylacetal (10 mL) was refluxed under N2. After 18 h, the reaction mixture was evaporated to dryness and the residue was recrystallised from iPr2O/CH2Cl2 to afford the title compound as a brown powder (9.94 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 2.66 (s, 6H, CH3), 2.70 (s, 6H, CH3), 5.37 (d, 1H, J=12.2 Hz, CH), 7.66 (d, 1H, J=12.2 Hz, CH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1([CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCC(N)(C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(N)(CO)CC1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
Lithium aluminum hydride powder (15.62 g., 0.412 mole) in dry tetrahydrofuran (THF) (600 ml.) was heated under reflux for 15 minutes, after which 4-amino-1-methylpiperidine-4-carboxylic acid (31.0 g., 0.196 mole) in the form of a dry powder was added portionwise under nitrogen, with efficient stirring. After the addition was completed, the reaction mixture was heated under reflux for four hours, cooled to 0° C. under nitrogen with efficient stirring, worked up by careful slow addition of water (20 ml.), 15% aqueous NaOH (20 ml.) and again water (10 ml.). The reaction mixture was filtered and the precipitate was extracted with boiling THF (3 ×150 ml.). The THF liltrate and the extracts were combined and the solvent removed at 25 mm to give a yellow viscous oil (28.0 g., 98.9% yield).