Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ccc(I)cc2s1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nc2ccc(I)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 6-iodobenzo[d]thiazole-2-thiol (0.5 g, 1.7 mmol) and potassium carbonate (0.23 g, 1.7 mmol) in THF (10 mL) was added methyl iodide (0.12 mL, 1.1 mmol). After stirring at rt overnight, the mixture was concentrated under reduced pressure to give a solid. The solid was partitioned between saturated aq sodium carbonate and DCM. The organic layer was dried over Na2SO4 and filtered, and concentrated under reduced pressure to give 6-iodo-2-(methylthio)benzo[d]thiazole as a off-white solid (0.4 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=1.2 Hz, 1H), 7.69 (dd, J=1.8, 8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 2.78 (s, 3H). LCMS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:41]([NH:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH3:31])[C:11]([CH:22]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24])=[C:12]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:43])[CH3:42]
Reactant: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (12 mg, 0.026 mmol) in CH2Cl2 (1 mL) was added triethylamine (50 μL) and acetic anhydride (10 μL) and trace DMAP. After 30 min, the reaction mixture was filtered and purified by reverse phase HPLC (MeCN/H2O w/0.1% TFA) to give 10 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.27 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.90 (s, 3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33ClNO4: 506.2; found: 506.0.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[N:5]1)#[N:2].[H-].[Na+].[CH3:19][N:20]1[C:24]([Cl:25])=[C:23]([C:26](N2C=CC=N2)=[O:27])[C:22]([Cl:33])=[N:21]1.O>C1COCC1>[F:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:16])[C:9]=1[C:6]1[CH:7]=[CH:8][N:4]([C:3](=[C:26]([C:23]2[C:22]([Cl:33])=[N:21][N:20]([CH3:19])[C:24]=2[Cl:25])[OH:27])[C:1]#[N:2])[N:5]=1
Reactant: N#CCn1ccc(-c2c(F)cccc2F)n1
Reactant: Cn1nc(Cl)c(C(=O)n2cccn2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)c(C(O)=C(C#N)n2ccc(-c3c(F)cccc3F)n2)c1Cl
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of 0.5 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole dissolved in 10 ml of THF was dropwise added to a suspension of 0.15 g of 55% sodium hydride in 10 ml of THF, at 50° C. After the resulting product was stirred for 30 minutes, a solution of 0.67 g of 1-(1-methyl-3,5-dichloropyrazole-4-carbonyl)pyrazole dissolved in 10 ml of THF was dropwise added thereto at 50° C. and then stirred overnight at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate and washed with a small amount of water. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropyl ether/ethyl acetate=3/1 to obtain 0.52 g of 2-{3-(2,6-difluorophenyl)pyrazol-1-yl}-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])=[CH:9][C:8]=1[Br:33].C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>ClCCl>[Br:33][C:8]1[CH:9]=[C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCN)c(OCC)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCNC(=O)C(C)C)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step b (117 mg), triethylamine (81 μl) and isobutyrylchloride (24 μl) in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 69 mg. MS-ESI: [M+H]+=610.4/612.4; HPLC: Rt=19.45 min. (method 1). Diast. ratio: 5:1
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[CH2:26]([SH:28])[CH3:27].C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:28][CH2:26][CH3:27])=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CCS
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCSC1=C(C(=O)c2ccc3c(c2Cl)S(=O)(=O)CCC3(C)C)C(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (1.75 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one is dissolved in 20 ml of tetrahydrofuran, and 0.11 g (1.75 mmol) of ethanethiol and 0.19 g (1.92 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for 2 hours, stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid and dried and the solvent was removed. This gave 0.4 g of beige crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]2=[O:29])=[C:4]2[N:10]=[CH:9][N:8](CC3C=CC(OC)=CC=3)[C:5]2=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]2=[O:29])=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC1CC(=O)N(Cc2c(Br)cnc3c2ncn3Cc2ccc(OC)cc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c(Br)cnc3[nH]cnc23)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution containing 1-{[6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x213 (0.5 g, 0.1 mmol), anisole (0.4 ml) and concentrated H2SO4 (0.2 ml) in trifluoroacetic acid (4 ml) is stirred in a flow of argon at 20° C. for 2 h. The homogeneous reaction mixture is added dropwise at 0° C. to a mixture of a saturated aqueous solution of NaHCO3 (50 ml) and ethyl acetate (50 ml). The organic layer is separated. The aqueous one (pH ˜8) is subjected to additional extraction with chloroform containing 10% of tert-butanol. The combined organic layers are dried with anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 0.31 g of 1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one 99.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13](C)[CH:14]=[O:15]>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]([NH:13][CH2:12][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:15]
Reactant: CN(C)C=O
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNC(=O)NCCSCc1[nH]cnc1C

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.6 g.) and 1,1-carbonyl di-imidazole (0.5 g.) in dimethyl formamide (12 ml.) was heated to reflux temperature whereupon the mixture solidified. After cooling, a small quanity of dimethyl formamide was added and the slurry was filtered to give the solid product which was washed with water, ethanol and ether and finally recrystallised from dimethyl formamide. Yield 0.5 g., m.p. 230°-234°.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[N:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)[S:10][CH:11]=2)=[CH:5][N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[CH:5]=[C:6]([C:7]3[N:8]=[C:9]([NH:12][C:13]4[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=4)[S:10][CH:11]=3)[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:3]2)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(-c3ccccc3)n2)cc1
Yield: 51.5 %

Procedure:
According to Scheme 12 Step 1: A solution of 4-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.33 mmol, 150 mg), phenylboronic acid (0.39 mmol, 48 mg), Pd(PPh3)4 (49 μmol, 57 mg) and a saturated aqueous solution of NaHCO3 (0.5 mL) in dioxane (0.5 mL) was stirred at 120° C. for 2 hours under microwave heating. The crude mixture was filtered through celite pad and washed with DCM. The filtrate was washed with water. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using DCM/AcOEt (100:0 to 70:30) to yield 4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.17 mmol, 77 mg, 52%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([N:16]([CH2:18][C:19]1[CH:24]=[C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]=[CH:21][C:20]=1[C:33](=[CH2:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:17])=[O:15])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[C:9]([O:13][C:14]([N:16]([CH2:18][C:19]1[CH:24]=[C:23]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:22]=[CH:21][C:20]=1[C:33]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:39]1)[CH3:17])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)cc2CN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.019 g, 0.473 mmol) in DMSO (2.5 mL), was added trimethylsulfoxonium iodide (0.284 g, 1.291 mmol). The mixture was stirred at rt for 2 h. To the solution was added 15E (0.187 g, 0.430 mmol) in DMSO (2.5 mL) to give a yellow solution. The mixture was stirred at rt for 1 h, quenched with sat. NH4Cl (10 mL), extracted with EtOAc (4×15 mL). Combined organic phase was washed with water (2×10 mL), brine (1×10 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15F (0.173 g, 90% yield) as a colorless syrup. MS (ESI) m/z: 449.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.34-7.50 (1H, m), 7.20 (1H, d, J=8.08 Hz), 6.83-6.96 (1H, m), 6.44 (1H, br. s.), 4.51 (2H, br. s.), 4.07 (2H, q, J=7.16 Hz), 2.82 (3H, br. s.), 1.35-1.72 (22H, m), 1.15 (3H, t, J=7.07 Hz).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:39])[CH:36]([CH3:38])[CH3:37])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:39][CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(CCCCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)CCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.2 ml of concentrated sulphuric acid in 1 ml of methanol with 130 mg (0.27 mmol) of 8-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methyloctan-3-ol in 1 ml of methanol and 1 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a yellowish oil (m=12 mg; Y=13%) is obtained.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[N:17]2[CH2:20][C:19](=[C:21]([S:42]([CH3:45])(=[O:44])=[O:43])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24](C(OC4C(F)=C(F)C(F)=C(F)C=4F)=O)[CH:23]=3)[CH2:18]2)=[CH:12][CH:11]=1.[C:53](OCC)(=[O:55])C>CN(C)C=O>[Cl:52][C:49]1[CH:48]=[CH:47][C:46]([CH:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:17]2[CH2:18][C:19](=[C:21]([S:42]([CH3:45])(=[O:44])=[O:43])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:53](=[O:55])[NH:1][N:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[CH2:20]2)=[CH:51][CH:50]=1
Reactant: CN1CCN(N)CC1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(NC(=O)c2ccccc2C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.083 g of 1-amino-4-methylpiperazine is added to a solution of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidine in 5 cm3 of dimethylformamide. The mixture is stirred for 20 hours at room temperature and then 40 cm3 of ethyl acetate are added. The organic phase is washed with 4 times 20 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated with 10 cm3 of ethyl ether, filtered and then dried. 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[(N-4-methylpiperazinylcarbamoyl)phenyl]methylene}azetidine is obtained in the form of a yellow solid melting at 162° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.20 (3H, s, NCH3), 2.40 (4H, m, 2 NCH2), 2.90 (4H, m, 2 NCH2), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.), 7.55 (2H, m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[C:5]([C:27]([F:30])([F:29])[F:28])[N:4]=1.C1COCC1>CO.[Pd]>[F:31][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:27]([F:30])([F:28])[F:29])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCc2ccccc2)c1NC(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)O)c1NC(C)C
Yield: 101.1 %

Procedure:
A mixture of 46.27 g (0.1 mol) of 3-methyl 5-benzyl 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (example 181 of U.S. Pat. No. 4,698,093) in 1.2 L of a 1:5 mixture of THF in methanol was hydrogenated using catalytic 5% Pd/C under 50 lb of hydrogen pressure for 48 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give 36 g of 3-methyl 5-hydrogen 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate. To a mixture of 34.7 g of this monoacid in 400 ml of carbon tetrachloride was added 23 g (0.11 mol) of phosphorus pentachloride. The reaction mixture was stirred at room temperature until HCl evolution stopped. The reaction mixture was held at reflux for 20 min and concentrated in vacuo affording 38.04 g of monoacid chloride as a yellow oil. A portion (3.75 g 0.01 mol) of this oil and 1.7 g (0.01 mol) of triethyl phosphite was heated to 160° C. and then cooled. The resulting oil was purified by HPLC (25% EtOAc in hexane) affording 2.09 g of (44%) of product as a thick yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].[OH-].[Na+].Cl>C(#N)C.N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)=[CH:4][CH:3]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(-n2nnnc2S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(-n2nnnc2S)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thirty grams of 1-(p-aminophenyl)-1,2,3,4-tetrazole-5-thiol was dissolved in 300 ml of acetonitrile and 20 ml of pyridine, and 16 ml of methacrylic acid chloride was added dropwise to the resulting solution with agitation. After the addition of the methacrylic acid chloride, the mixture was agitated for 1 hour at room temperature. Thereafter, a 10% aqueous solution of sodium hydroxide was added and the mixture was agitated for a white. The mixture was rendered weakly acidic with dilute hydrochloric acid and the end compound was obtained as a white crystal in an amount of 29.4 g (yield, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 122.9 %

Procedure:
A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (0.600 g, 1.45 mmol) in DME (10.0 mL) was reacted with 4-trifluoromethylbenzene boronic acid (0.55 g, 2.91 mmol), Pd(PPh3)4 (0.70 g, 0.14 mmol), and Na2CO3 (2.0N, 3.50 mL, 3.64 mmol) by the general procedure D to give 0.850 g of 2-(2-amino-5-chloro-benzoylamino)-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a brown oil.
Reaction SMILES: S1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:20]([O-:23])([O-])=[O:21].[Na+].[Na+]>C(Cl)(Cl)Cl>[S:20]1(=[O:23])(=[O:21])[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1
Reactant: N#CC1CCSCC1
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#CC1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A chloroform solution of tetrahydro-2H-thiopyran-4-carbonitrile was dropwise added to a chloroform solution of 77% m-chloroperbenzoic acid at 0° C., followed by stirring at room temperature for 3 hours. An excess amount of an aqueous saturated sodium sulfite solution was added, followed by work-up to obtain tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([OH:12])=O.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:12]
Reactant: O=C(O)C#Cc1ccccc1F
Reactant: CCOC(=O)CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 0° C. slurry of 3-(2-fluorophenyl)prop-2-ynoic acid (151 g, 0.92 mol) in CH2Cl2 (3L) was added DMAP (118 g, 0.96 mol, 1.05 equiv), followed by sarcosine ethyl ester hydrochloride (148 g, 0.96 mol, 1.05 equiv), and NMM (233 g, 2.3 mol, 2.5 equiv). The resulting clear solution was allowed to warm to room temperature and was maintained for 17 h. The reaction mixture was washed with a 2N HCl solution (4×500 mL). The aqueous layers were combined and the mixture was adjusted to pH 2 using conc. H2SO4, then back-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with a 10% H2SO4 solution (2×500 mL), dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (174 g, 72%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.61; 1H NMR (CDCl3; of rotomeric mixture) δ 1.27 (t, J=7.2 Hz, 3H), 3.07 (s, 1.4H, N—CH3), 3.36 (s, 1.6H, N—CH3), 4.17-4.27 (m, 3.2H), 4.41 (s, 0.8H, N—CH2), 7.06-7.17 (m, 2H), 7.37-7.58 (m, 2H); 13C NMR (CDCl3; of rotomeric mixture) δ 14.00, 14.03, 33.5, 37.2, 48.0, 52.5, 61.3, 61.5, 83.6, 84.3, 85.7 (d, JC−F=9.9 Hz, 1C), 108.9 (d, JC−F=15.5 Hz, 1C), 109.1, (d, JC−F=15.5 Hz, 1C), 115. (d, JC−F=10.4 Hz, 1C), 115.6 (d, JC−F=10.4 Hz, 1C), 124.2, 132.0 (d, JC−F=7.8 Hz, 1C), 132.1 (d, JC−F=7.8 Hz, 1C), 134.10, 134.15, 154.6, 163.3 (d, JC−F=254.4 Hz, 1C), 168.1, 168.5; HPLC ES-MS m/z (rel abundance) 264 (MH+, 75%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](O)=[CH:7]2.[CH3:13][CH2:14][O-:15].[Na+].BrCC[CH2:20][C:21]#[N:22]>CCO.O>[C:21]([CH2:20][CH2:13][CH2:14][O:15][C:7]1[C:8]2[C:3](=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1)#[N:22]
Reactant: Oc1ccc2c(I)cccc2c1
Reactant: N#CCCCBr
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCOc1cccc2c(I)cccc12
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
To a stirred mixture of 5-iodo-2-naphthol (300 mg, 1.11 mmol) in EtOH (7 mL) was added NaOC2H5 (90.7 mg, 1.2 equiv) and, after 10 min, 4-bromobutyronitrile (0.22 mL, 2.0 equiv). The mixture was then heated at reflux for 2 h. It was diluted with water, extracted with dichloromethane, washed with brine and dried (Na2SO4). Concentration and chromatography on silica gel (hexane/ethyl acetate=4:1) gave 1-(cyanopropyloxy)-5-iodonaphthalene (77 mg, 20.6%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCC1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: OC(CCl)CN(Cc1ccccc1)Cc1ccccc1
Yield: 69.7 %

Procedure:
49.3 g (0.25 mol) of dibenzylamine and 25.4 g (0.275 mol) epichlorohydrin are stirred under nitrogen at 85°90° C. for 3 hours. The golden yellow oil obtained is distilled in a high vacuum. 50.5 g (70%) of a colourless oil are obtained.