Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C@H:5]1[CH2:9][NH:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:19](=O)([O:35]N1C(=O)CCC1=O)[O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>O1CCOCC1.O>[CH:33]1[C:34]2[CH:22]([CH2:21][O:20][C:19]([N:8]3[CH2:9][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6][C@H:7]3[C:10]([OH:12])=[O:11])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CCO[C@H]1CN[C@H](C(=O)O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.9 %

Procedure:
(2S,4R)-4-Ethoxypyrrolidine-2-carboxylic acid hydrochloride (Compound SP820) (45 g, 230 mmol) was dissolved in a mixture of 1,4-dioxane (500 ml) and water (500 ml), potassium carbonate (79.4 g, 574 mmol) and (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (Fmoc-OSu, 69.8 g, 207 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 3 with an aqueous potassium bisulfate solution and extracted with ethyl acetate. The resulting organic extract was washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to afford (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-ethoxypyrrolidine-2-carboxylic acid (Compound SP813, Fmoc-Hyp(Et)-OH) (90.7 g, 103%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][NH:16]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([N:16]2[CH2:17][CH2:18][CH:19]3[CH:24]([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:15]2)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(Cl)c1ccc2cccnc2c1O
Reactant: C1CCC2CNCCC2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2cccnc2c1O)N1CCC2CCCCC2C1
Temperature: 50 °C

Procedure:
A solution of 8-hydroxyquinoline-7-carbonyl chloride of Preparation 2 (70 mg, 0.35 mmol) and decahydroisoquinoline (62.6 mg, 0.45 mmol) in THF (8 mL) and DIPEA (259 mg, 2.0 mmol) was stirred and heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM:MeOH 98:2) and then by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (49 mg, 0.16 mmol) as a off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:18])C(=O)C1.OS(O)(=O)=O.O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a mixture of 1-(2-aminophenyl)ethanone (5.0 g, 0.037 mol) in dichloromethane (60 mL) was added NBS (7.3 g, 0.04 mol). The resulting mixture was cooled to 0° C. followed by the addition of H2SO4 (0.05 mL). It was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water and extracted with dichloromethane, dried over MgSO4. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes to afford the titled compound (4.6 g, 58%) as a yellow solid. m.p 87-89° C. 1H NMR (400 MHz, CDCl3): δ 2.56 (s, 3H), 6.31 (s, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.33 (dd, J=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20](I)=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][C:19]=3[C:20]([C:30]#[N:31])=[CH:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(I)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Reactant: [C-]#N
Agent: [Fe+2]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Yield: 28.7 %

Procedure:
4-(4-benzyloxy-3-isopropylphenoxy)-7-iodo-5-methylindane (214 mg), potassium cyanide (60 mg), bis(dibenzylidenacetone)palladium (4 mg), 1,1′-bis(diphenylphosphino) ferrocene (8 mg), and 1-methyl-2-pyrrolidone (2 mL) were stirred under an argon atmosphere at 80° C. overnight. Adding water, the reaction mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate) to give the title compound (49 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9]([OH:11])=O)=[O:6])[CH3:3].[C@H:24]12[CH2:29][C@H:28]1[CH2:27][C@@H:26]([C:30]([NH2:32])=[O:31])[NH:25]2.CS(O)(=O)=O.Cl.ON1C2C=CC=CC=2N=N1>>[NH2:32][C:30]([C@@H:26]1[CH2:27][C@H:28]2[C@H:24]([CH2:29]2)[N:25]1[C:9](=[O:11])[C@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:23])=[O:6])=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C(N)=O)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
A coupling reaction is then used to couple (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, (Formula VI) to (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Formula J) methanesulfonic acid salt or HCl salt in the presence of 1-hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3-(aminocarbonyl)-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula K). Formula K compound is subjected to dehydration by treating compound K with organic base such as pyridine or triethylamine, and trifluoroacetic anhydride or other dehydrating agent such as phosphorus oxychloride (POCl3) or cyanuric chloride, and then subjecting the reaction to hydrolysis by cooling to from about 25 to about 40° C. and treating with sodium hydroxide or other strong base such as KOH or LiOH to form Compound L. 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula L), which is then deprotected to form the dipeptidyl peptidase IV inhibitor (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula M).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH2:13][S:14][CH2:15][C:3]1=2.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2=[CH:13][S:14][CH:15]=[C:3]12
Reactant: Cn1c2c(c(=O)c3ccccc31)CSC2
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Cn1c2ccccc2c(=O)c2cscc21
Yield: 70 %

Procedure:
2.17 parts of 1,4-dihydro-4-methylthieno-[3,4-b]-quinolin-9(3H)-one are reacted with 0.88 part by volume of sulfuryl chloride in 25 parts by volume of methylene chloride at 0° C. for 0.5 hour. The end product is isolated from the reaction mixture by the method described in Example 5c. 1.50 parts (70% of theory) of 4-methylthieno-[3,4-b]-quinolin-9(4H)-one of the melting point 188°-190° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[CH3:17][NH:18][CH3:19]>O1CCCC1>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:18]([CH3:19])[CH3:17])=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Reactant: CNC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in 2M dimethylamine in tetrahydrofuran (2 ml) and stirred for 18 hours at 20° C. The reaction was evaporated to dryness in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:15]([O:19][C:20]([N:22]1[CH2:27]CC(=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N.CO>>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][C:3]2[N:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 70 °C

Procedure:
1-Methyl-3,5-dinitro-1H-pyridin-2-one (6.0 g, 30.15 mmol), and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, 33.15 mmol) were added to a 2 M solution of NH3 in MeOH (225 mL, 452.3 mmol) in a sealed tube. The reaction was heated to 70° C. for 16 h. The solvent was removed and the yellow solid was recrystallized from MeOH affording 3-nitro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester as tan solid.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([Cl:20])[CH:22]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: Cc1nc(C(C)(C)NC(=O)c2cccc(Br)n2)no1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Cc1nc(C(C)(C)NC(=O)c2cccc(-c3ccc(F)c(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 267 b, 6-bromo-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 267a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials, LC-MS (UV peak area/ESI) 91%, 375.1018 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25](=[O:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][Mg]Br.C(OCC)(=O)C>C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([OH:32])([CH3:42])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: C[Mg]Br
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)CC2CCCC2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone (160 mg, 0.269 mmol) in anhydrous THF (10 mL) at 0° C. was added methylmagnesium bromide (3.0 M solution in THF, 0.359 mL, 1.07 mmol). After stirring for 30 minutes the solution was warmed to room temp and stirred for 1.5 hours. After 1.5 hours solution was portioned between 2 N HCL (10 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 10 minutes before the layers were separated. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organics layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. (160 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H) 7.67(s, 2H) 7.38 (m, 3H) 5.32 (d, J=16.6 Hz, 1H) 5.01 (d, J=16.6 Hz, 1H) 4.78 (s, 2H) 4.13 (s, 3H) 1.92 (dd, J=5.4 Hz, J=5.4 Hz) 1.80 (dd, J=5.81 Hz, J=6.24 Hz) 1.64 (m, 2H) 1.59 (s, 3H) 1.54 (m, 3H) 1.35 (m, 2H) 0.88 (m, 2H). LC-MS Calc. 609.5, found 610.5 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccc2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1-naphthyl)-1-hexanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-naphthyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [NH:1]1C=CC=N1.ClC1C(C(NC2C=CC=CC=2[C:22]2[CH:27]=[C:26]([F:28])[C:25]([N:29]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]3)=[C:24]([F:38])[CH:23]=2)=O)=CC=CN=1.O.O.[Sn](Cl)Cl>C(O)C>[F:38][C:24]1[CH:23]=[C:22]([NH2:1])[CH:27]=[C:26]([F:28])[C:25]=1[N:29]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]1
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1

Procedure:
A mixture of 1-(2,6-difluoro-4-nitrophenyl)-3-trifluoromethyl)-1H-pyrazole (i.e. the product of Step A; 2.39 g, 8.15 mmol) and tin(II) chloride dihydrate (9.33 g, 41.3 mmol) in ethanol (173 mL) was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with 1 N aqueous sodium hydroxide, and then water. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to provide the title compound (2.00 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)#[CH:18]>>[S:21]1[CH:22]=[CH:23][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20]1
Reactant: C#Cc1ccsc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccsc3)c2c2ccccc12
Yield: 71.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 3-ethynyl-thiophene (70 mg, 0.65 mmol) to provide 167 (93 mg, 71% yield) as a white solid. LC-MS (M+H=303, obsd.=303).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1.O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Temperature: -75 °C
Reaction time: 4 h

Procedure:
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 63) (5 g) in tetrahydrofuran (75 ml) was cooled to 0° C. then treated with sodium hydride (60% oil dispersion, 1.23 g) portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) was added over 25 min maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added over 10 min and the mixture was stirred at −70° C. for 4 h. Water (20 ml) was added and the mixture was allowed to warm to 5° C. The solvent was removed under vacuum and the residue was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in dichloromethane/ethyl acetate and purified by column chromatography on silica eluting with dichloromethane:ethyl acetate (95:5 to 0:100) then methanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(O)C.Cl>C(O)C>[ClH:1].[CH3:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[N:11]=1
Reactant: Cc1ccccc1N
Reactant: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(Nc3ccccc3C)nc(N(C)c3ccccc3)c2c1
Yield: 57.7 %

Procedure:
A mixture of 2-chloro-4-(N-methylphenylamino)-6methoxyquinazoline (5.4 g, 0.027M), o-toluidine (4.28 g, 0.04M) in ethanol (50 ml) was heated in a Berchof pressure vessel at 140° for 5 hours (maximum pressure 40 psi). After cooling, ethanol/HCl was added and the solid which crystallised out was filtered off and recrystallised from isopropanol/ether to yield the title compound (4.23 g, m.p. 258°-260°).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][CH:7]([CH3:10])[CH2:8][OH:9].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>>[C:14]([O:9][CH2:8][CH:7]([Cl:6])[CH3:10])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: CC(Cl)CO
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCC(C)Cl
Yield: 69.2 %

Procedure:
0.7 g of sodium acetate was added to 7.5 g of 2-chloropropanol, to which 7.4 g of diketene was added dropwise with stirring while the reaction temperature was maintained at 40°-50° C. The reaction mixture was stirred at room temperature for an additional 2 hours and then worked up in the manner described in Referential Example 4. The resulting crude product was purified by distillation to obtain 9.8 g of 2-chloropropyl acetoacetate.
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([O-])(=[O:20])C.[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>C(#N)C>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][S:14]1=[O:20])[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCC12OCC(CCC)(CS1)CS2
Reactant: CC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C#CCCCCC12OCC(CCC)(CS1)CS2=O

Procedure:
A mixture of 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo-[2.2.2]octane (0.75 g., 1 equivalent), anhydrous sodium acetate (2.0 g.) and 3-chloroperbenzoic acid (85%, 1.12 g. 2.5 equivalents) was stirred at 20° in dry acetonitrile (50 ml.) for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with sodium hydrogen carbonate solution, water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. After purification by chromatography on silica (eluting with ethyl acetate), 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo[2.2.2]octane-6-oxide was obtained as a colourless solid (0.35 g.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]1[N:13]=[C:11]([CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=2)[O:12][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(C=Cc2nc(CCl)co2)c1

Procedure:
2.0 g (9.3 mmol) 3-(3-Trifluoromethyl-phenyl)-acrylamide, 4.13 g (32.5 mmol) 1,3-dichloro acetone and 20.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by flash column chromatography (heptanes/ethyl acetate 2:1). Yield: 1.92 g (72%) 4-Chloromethyl-2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[C:25]([Cl:34])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[C:25]([Cl:34])[CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Cl
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(OC(F)(F)F)c(Cl)c1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 59 %

Procedure:
The titled compound was prepared in 59% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 4-bromomethyl-2-chloro-1-trifluoromethoxy-benzene (72 mg, 0.249 mmol) according to the procedure described for Example 3: 1H NMR (500 Mz, DMSO) δ 7.81 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.6), 7.48 (br s, 1 H), 7.44–7.35 (m, 4 H), 6.70 (br s, 1 H), 4.56 (ABq, 2 H, Δv=106, Jab=17.1), 3.88 (m, 1 H), 2.82 (m, 1 H), 2.44 (m, 1 H), 1.80 (m, 1 H), 1.67 (m, 2 H), 1.39–1.22 (m, 3 H), 0.89 (m, 1 H); MS m/e 547.2 (M+Na)+.