Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[NH:4][CH2:5][CH2:6][O:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[N:4]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][CH2:6][O:7]2
Reactant: ICCOc1ccccc1
Reactant: CC12OCCNC1Cc1c[nH]c3cccc2c13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC12OCCN(CCOc3ccccc3)C1Cc1c[nH]c3cccc2c13
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of 4,6,6a,8,9,10a-hexahydro-10a-methyl-7H-indolo[3,4-gh][1.4]benzoxazine (85 mg, 0.37 mmol) in DMF (5 ml) were added potassium carbonate (255 mg, 1.9 mmol) and 1-iodo-2-phenoxyethane (99 mg, 0.4 mmol). The mixture was heated at 60° C for 24 hours. After completion of the reaction, the reaction mixture was added to a mixture of ice water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (2:1), to afford 59 mg (46%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24](O)([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([C:19]2[S:23][C:22]([CH:24]([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)C)s2)c1
Temperature: 60 °C
Yield: 56 %

Procedure:
To a stirred solution of 2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl}amino]phenyl)-1,3-thiazol-2-yl]propan-2-ol (Example 4, 58 mg, 0.15 mmol) in DCM (1.5 mL) were added Et3SiH (0.18 mL, 1.1 mmol) and TFA (0.17 mL, 2.2 mmol). The reaction mixture was heated to 60° C. for 3 hr. Additional Et3SiH (0.18 mL) and TFA (0.11 mL) were added and the reaction was then heated to 80° C. for 1 d. The mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and washed with saturated aqueous NRHCO3 solution, water, and brine. The solution was dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography to give N-{3-methyl-5-[2-(1-methylethyl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (31.7 mg, 0.084 mmol, 57.3% yield) as a white solid. APCI: [M+H]+ m/z 379.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 3.27 (dt, J=6.9, 13.7, 1H), 2.31 (s, 3H), 1.34 (d, J=6.9, 6H). rhSYK activity=+++
Reaction SMILES: [CH2:1]([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][NH2:3].[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=O.[NH:18]1[CH:22]=[C:21]([CH:23]=O)[N:20]=[CH:19]1>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:10][NH:3][CH2:2][CH2:1][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:23][C:21]1[N:20]=[CH:19][NH:18][CH:22]=1
Reactant: NCCCNCCCN
Reactant: O=Cc1ccccn1
Reactant: O=Cc1c[nH]cn1
Solvent: CCO
Product: c1ccc(CNCCCNCCCNCc2c[nH]cn2)nc1

Procedure:
This compound was synthesized as described in Example 4 by using 3,3'-diaminodipropylamine (4) (0.655 g, 0.005 mol) in dry ethanol and the two aldehydes pyridine-2-carboxaldehyde (2) (0.535 g, 0.005 mol) and imidazole-4-carboxaldehyde (34) (0.48 g, 0.005 mol) in that order. After catalytic hydrogenation and purification by silica gel column chromatography, the pure free base (36) was obtained (0.79 g). The product was transformed into the hydrochloride salt as described in Ex: 4
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (1 g, 5 mmol) and triethylamine (1.05 ml, 7.5 mmol) in THF (30 mL) at 0° C. was slowly added 4-chloro-benzoyl chloride (0.77 ml, 6 mmol). The reaction mixture was stirred from 0° C. to room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C:25]1C(C(OC)=O)=NC(C2C=NC=CC=2)=NC=1NC1C=CC=CC=1.N>CO>[C:9]1([N:8]2[CH:25]=[N:1][C:2]3[C:7]2=[N:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:4][C:3]=3[C:21]([NH2:23])=[O:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)c1nc(-c2cccnc2)nc(Nc2ccccc2)c1N
Reactant: COC(=O)c1nc(-c2cccnc2)nc(Nc2ccccc2)c1N
Agent: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccnc2)nc2c1ncn2-c1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-Amino-6-(phenylamino)-2-(3-pyridyl)pyrimidine-4-carboxamide. A solution of methyl 5-amino-6-(phenylamino)-2-(3-pyridyl)pyrimidine-4-carboxylate (0.123 g, 0.383 mmol) in anhydrous methanol (15 mL) was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 hours the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting solids dried under vacuum to provide the title compound (0.117 g, 0.383 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J=1.6, 1H), 8.93 (s, 1H), 8.67 (dt, J=8.0, 2.0, 1H), 8.58 (dd, J=4.8, 1.6, 1H), 8.43 (s, 1H), 7.85 (d, J=8.4, 2H), 7.63 (s, 1H), 7.42-7.47 (m, 3H) 7.23 (s, 2H), 7.11 (t, J=7.6, 1H); MS (ESI) m/z 307.3 [M+1]+; mp 285-288° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[ClH:29]>CO.ClCCl.O1CCOCC1>[ClH:29].[ClH:29].[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:28])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-piperidinyl}carbamate (8.72 g, 22.36 mmol) in methanol (90 ml) and dichloromethane (150 mL) was treated with 4 M hydrogen chloride in 1,4-dioxane (150 mL) (added in a slow stream, some exotherm and rapid precipitation observed) and stirred at room temperature for 2.5 h. The mixture was evaporated to dryness and the residue was triturated with ether. The solid was filtered off, washed with ether and dried to give the amine salt as a grey-green solid (8.06 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>COCCOC>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)I
Reactant: Cc1cc(O)nc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc(OC(C)C)nc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KTB (222 mg) was added to a suspension of 5-bromo-4,6-dimethylpyridin-2-ol obtained in Preparation Example 23(1) (400 mg) in DME (2 mL), and the mixture was stirred at room temperature for 30 minutes. Potassium carbonate (192 mg) and 2-iodopropane (572 mg) were added to the reaction mixture. The mixture was heated under reflux overnight. The reaction mixture was cooled to mom temperature, and the insoluble matter was removed by filtration and washed with DME. The filtrate was concentrated under reduced pressure. Chloroform was added to the residue. The solution was washed with a 0.1 N aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 50%) to give the title compound (133.9 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:14]=[CH:15][C:16]([OH:18])=O)([CH3:10])[CH3:9].[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH2:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C)C=O>[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH:32][C:16](=[O:18])[CH:15]=[CH:14][C:13]1[CH:12]=[C:11]([C:8]([CH3:7])([CH3:10])[CH3:9])[C:21]([OH:22])=[C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:19]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)N(N)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=CC(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Oxalyl chloride (2.9 g, 0.023 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid (4.3 g, 0.016 mole) in methylene chloride (30 ml) and N,N-dimethylformamide (0.5 ml). After one hour the solvent is removed in vacuo. The residue is dissolved in methylene chloride (30 ml) and added dropwise to a stirred 0° C. solution of 1,1-dimethylethyl hydrazinecarboxylic acid (4.5 g, 0.034 mole). After the addition is complete, the mixture is allowed to warm to room temperature and stir 18 hours. The mixture is concentrated in vacuo and the residue dissolved in methylene chloride (50 ml) and washed with aqueous 2M HCl, saturated aqueous NaCl, and dried MgSO4. Filtration and concentration gives a solid which was recrystallized from ethyl acetate/isopropyl ether to provide 4.6 g (6.1 g theor., 76% ) of 1,1-dimethylethyl 2- [3- [3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylic acid, mp 184° C.
Reaction SMILES: [B].[OH:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:17][O:18]C)[C:4]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21].O>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[C:8]([C:13]([F:14])([F:16])[F:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:17][OH:18])[C:4]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21]
Reactant: COCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: [B]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)c1c(CO)nc2c(C(F)(F)F)cccc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 4 ml of boron tribomide in 30 ml of methylene chloride was added with stirring at -70° C. to a solution of 2.88 g of the product of Example 3 in 75 ml of methylene chloride and the mixture stood overnight with stirring while the temperature was allowed to rise to -20° C. The mixture was poured into 500 ml of ice and water and the mixture was stirred for 20 minutes and was vacuum filtered. The product was washed with water until the pH was 5 to 6 and was dried under reduced pressure at 100° C. The product was dissolved in refluxing dimethylformamide and the solution was cooled, iced and vacuum filtered. The product was washed with dimethylformamide and then with ether and dried under reduced pressure at 120° C. to obtain 2.3 g of 4-hydroxy-2-hydroxymethyl-N-(2-thiazolyl)-8-trifluorometyl-3-quinoline-carboxamide melting at 280° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[NH:7][CH:8]=[N:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:16][O:17][C:18]([C:20]1[S:24][C:23](Br)=[N:22][C:21]=1[Br:26])=[O:19].O>CN1CCCC1=O>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]([N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=3[N:7]=[CH:8]2)=[N:22][C:21]=1[Br:26])=[O:19]
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: COC(=O)c1sc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 5,6-Dimethoxy-1H-benzimidazole (1.0 g, 5.65 mmol) in 1-methyl-2-pyrrolidinone (10 ml) at 0° C. was added NaH (60% dispersion; 339 mg, 8.475 mmol). After gas evolution had stopped, 2,4-Dibromo-thiazole-5-carboxylic acid methyl ester (1.7 g, 5.65 mmol) was added. The resulting solution was stirred at ambient temperature for 1 hr. 50 ml water was added. The suspension was stirred for 10 min and filtered to afford 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (1.6 g, 73%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 3H), 3.98 (s, 3H), 4.03 (s, 3H), 7.32 (s, 1H), 7.58 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[N:34]1([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42]#[N:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:27]=1)[CH2:6][N:7]([CH3:24])[CH:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:10]([C:21]([N:37]2[CH2:36][CH2:35][N:34]([C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42]#[N:43])[CH2:39][CH2:38]2)=[O:22])[CH2:9]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 111 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (73.1 mg) in 111% yield as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3ccccc23)ccc1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
A 0° C. solution of 700 mg (1.80 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 3-methyl-4-methoxyphenyl ketone (Part B) in 25 mL of CH2Cl2 was treated with 7.2 mL of BBr3 (1.0 M in CH2Cl2). The reaction was stirred at 0° C. for 6 h, then cooled to −78° C., and was treated carefully with 50 mL of MeOH. The mixture was allowed to warm to room temperature over 1.5 h, and the volatiles were evaporated in vacuo. The dark red residue (monomethyl ether) was taken up in 75 mL dichloroethane and was treated with AlCl3 and ethanethiol according to the conditions of Example 1, Part D to afford 675 mg of an oil. Purification by radial chromatography (SiO2; gradient of 20-30% EtOAc in hexanes) afforded 410 mg (1.14 mmol; 63%) of the title compound as an orange solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17].[CH:20]1([C:23]2[C:32]([CH:33]=[O:34])=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C1COCC1>[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH2:17][CH:33]([C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:34]
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Butyllithium (1.64M hexane solution, 7.54 ml, 12.4 mmol) was added to a THF (40 ml) solution of diisopropylamine (1.25 g, 12.4 mmol) at -78 ° C., and the mixture was stirred for 15 minutes. Thereto was added a THF (20 ml) solution of N-methoxy-N-methylacetamide (1.27 g, 12.3 mmol) at -78 ° C., and the resulting mixture was stirred at -78 ° C. for 15 minutes. To this mixture was added a THF (40 ml) solution of 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (3.00 g, 10.3 mmol). The reaction mixture was stirred at -78 ° C. to room temperature over a period of 3 hours before quenching with water and extraction with diethyl ether. The ethereal organic layer was washed with saturated sodium chloride aq solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give N-methoxy-N-methyl-3 -{2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl}-3-hydroxypropanamide (3.70 g, 91% yield).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:15]=1[C:16](OC)=[O:17].O.[NH2:39][NH2:40].C(N(CC)CC)C>O1CCOCC1.O>[NH2:39][N:40]1[C:16](=[O:17])[C:15]2[C:14](=[CH:23][CH:22]=[C:21]([C:24]([C:26]3[N:34]4[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]4)=[C:28]([O:35][CH3:36])[C:27]=3[CH3:37])=[O:25])[CH:20]=2)[NH:13][C:5]1=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)n(N)c(=O)c3c2)n2ccccc12
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
0.123 g (0.41 mmol) of triphosgene is added, under an inert atmosphere at ambient temperature, to 0.2 g (0.6 mmol) of methyl 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate in 10 ml of dioxane. After stirring for 10 minutes, 58 μl (1.2 mmol) of hydrazine hydrate and 0.4 ml (3 mmol) of triethylamine are added. The reaction medium is stirred for 3 hours and then hydrolysed with water. The aqueous phase is extracted with ethyl acetate. The organic phase obtained is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 16 mg of a yellow solid are obtained.
Reaction SMILES: C(N)(=S)C1C=CC=CC=1.[CH2:10]([C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[CH:25][CH:24]=1)[CH3:11].[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>>[CH2:10]([C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=1)[CH3:11]
Reactant: CCCCNCCCC
Reactant: CCc1sc(-c2ccccc2)nc1-c1ccc(OCCCCl)cc1
Agent: NC(=S)c1ccccc1
Product: CCCCN(CCCC)CCCOc1ccc(-c2nc(-c3ccccc3)sc2CC)cc1

Procedure:
The title compound was prepared according to Example 1, using p-hydroxybutyrophenone (20 g, 0.12 mol) in place of p-hydroxyacetophenone and 1-bromo-3-chloropropane (48 ml, 0.48 mol) to give 25 g (85% yield) of p-chloropropoxybutyrophenone as an oil. 1H NMR (CDCl3): δ7.92 (d, J=8.9 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.73 (t, J=6.3 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.23 (m, 2H), 1.78 (m, 2H), 0.99 (t, J= 7.0 Hz, 3H). Bromination (5 ml, 0.10 mol) followed by condensation with thiobenzamide (10 g, 73 mmol) of this product as described in Example 1 afforded 5-ethyl-4-(4-chloropropoxyphenyl)-2-phenylthiazole in 48% yield (15 g) as a white solid, mp 117°-119° C. Treatment of this product (5.1 g, 11 mmol) with dibutylamine in accordance with Example 1 gave 4.4 g (83% yield) of the free base of the title compound which was converted to the HCl salt, mp 128°-131° C. IR(KBr): 3400, 2610, 1620 cm-1, MS: 451(MH+). 1H NMR (CD3OD): δ7.96-7.02 (m, 9H), 4.12 (t, J=5.8 Hz, 2H), 3.38-2.76 (m, 8H), 2.20 (m, 2H), 1.75-1.18 (m, 14H), 0.91 (m, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[N:6][OH:7].[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:7][N:6]=[C:5]([Cl:10])[C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)C#CC=NO
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#CC(Cl)=NO
Reaction time: 4 h

Procedure:
To a solution of 3-trimethylsilylprop-2-ynal oxime (Carreira, Erick M.; Lohse-Fraefel, Nina, Organic Letters, Volume 7, Issue 10, 2005, Pages 2011-20141, 68 g, 11.9 mmol) in 11.9 mL of DMF stirred at r.t. was added N-chlorosuccinimide (1.99 g, 14.8 mmol). After 4 h stirring, the solution was poured into water and extracted with Et2O. After the usual work-up, the residue (2.09 g) was used as it was for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:38])[C@H:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(Cc3ccccc3)C2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H](Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(Cc3ccccc3)C2)cc1
Yield: 66.1 %

Procedure:
2-[4-[[(3S)-1-Benzyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (25 ml), and the resultant solution was cooled to room temperature with stirring to settle crystals. Subsequently, sodium ethoxide (100 mg, 1.5 mmol) was added thereto, followed by stirring at the same temperature for one hour, then sodium ethoxide (100 mg, 1.5 mmol) was further added, followed by stirring for 15 hours. The crystals were collected through filtration to obtain 3.3 g of the title compound (66% yield). The obtained crystals had a diastereomer purity of 82% under HPLC analysis conditions. The crystals were dissolved in acetic acid ethyl ester (75 ml), and washed three times with water (50 ml). The resultant organic layer was concentrated under reduced pressure, and the residue was recrystallized twice from ethanol (31 ml, 23 ml) to obtain 2.1 g of the title compound (43% yield). The diastereomer purity of the crystals was 99.1%.