Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.O=[C:10]1[CH2:15][CH2:14][S:13][CH2:12][CH:11]1[C:16](OCC)=O.C(O)(=[O:23])C>>[CH3:8][S:7][C:4]1[NH:5][N:6]2[CH2:16][C:11]3[CH2:12][S:13][CH2:14][C:15](=[O:23])[C:10]=3[N:1]=[C:2]2[N:3]=1
Reactant: CCOC(=O)C1CSCCC1=O
Reactant: CSc1n[nH]c(N)n1
Reactant: CC(=O)O
Product: CSC1=NC2=NC3=C(CSCC3=O)CN2N1
Reaction time: 1 h
Yield: 63 %

Procedure:
1.30 g (0.01 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole are dissolved in 6 ml of acetic acid, then 1.88 g (0.01 mole) of ethyl 4-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-3-carboxylate are added and the reaction mixture is boiled for 60 minutes. The precipitated product is filtered off from the hot solution and washed with i-propanol. The 1.6 g (63%) of 2-methylthio-5,6,8,9-tetrahydrothiopyrano[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one thus obtained are dissolved in 12 ml of hot 10% sodium hydroxide solution and after cooling down the precipitated 2-methylthio-5,6,8,9-tetrahydrothiopyrano[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one sodium salt is filtered off (melting point: higher than 350° C.), then dissolved in 30 ml of distilled water. Thereafter the solution is made highly acidic with the aid of acetic acid and the 2-methylthio-5,6,8,9-tetrahydrothiopyrano[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one is precipitated again.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH3:16].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.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.C1(C)C=CC=CC=1>[Br:7][C:6]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][CH:20]=2)=[N:3][S:4][C:5]=1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[CH3:14])=[O:10]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Reactant: CCOc1ccc(B(O)O)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: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2Br)cc1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
Degas a solution of (R,R)—N-[3,4-dibromoisothiazol-5-yl]-2-methylcyclopropane-carboxamide (0.500 g, 1.471 mmol), (4-ethoxyphenyl)boronic acid (0.485 g, 2.941 mmol), DMF (3 mL) and toluene (29 mL) with nitrogen. Add sodium carbonate (2 M) (4.41 mmol) and Pd(PPh3)4 (0.255 g, 0.221 mmol); then seal under nitrogen. Heat at 60° C. overnight. Add 100 mg of Pd(PPh3)4 and heat for 1 more day. Dilute with EtOAc and wash with brine. Separate and evaporate. Chromatography on silica gel, eluting with 15-50% EtOAc in hexane, followed by crystallization from EtOAc and hexane affords (R,R)—N-[4-bromo-3-(4-ethoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 53.5% ES-MS: 380.0 (m+1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>ClCCl>[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:3]([CH3:4])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(I)cc1

Procedure:
A suspension of dimethylamine hydrochloride (2.45 g, 30 mmol) in dichloromethane (150 ml) was cooled in an ice/methanol bath and then treated with triethylamine (6.0 g, 59 mmol) followed by 4-iodobenzoyl chloride (8.0 g, 30 mmol) portionwise with stirring under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 30 minutes before the solution was washed with water (2×100 ml). The organic layer was separated, dried over sodium sulphate, and evaporated under reduced pressure to give the title compound as a light beige coloured solid (7.73 g, 94%).
Reaction SMILES: C(O[CH:4]([O:8]CC)[CH2:5][CH:6]=[CH2:7])C.N1[CH:15]=[CH:14][CH:13]=[CH:12]1.[C:16](O)([C:18](F)(F)F)=O>>[CH2:14]([C:15]1[CH:7]=[CH:6][C:5]([CH:4]=[O:8])=[CH:18][CH:16]=1)[CH:13]=[CH2:12]
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc[nH]c1
Reactant: C=CCC(OCC)OCC
Product: C=CCc1ccc(C=O)cc1
Yield: 456.9 %

Procedure:
5-Allyldipyrromethane (24). Following a standard procedure,40,41 a solution of 3-butenal diethylacetal (4.00 g, 27.7 mmol) in pyrrole (194 mL, 2.77 mol) at room temperature under argon was treated with TFA (467 μL, 2.77 mmol) for 10 min. TEA (221 μL, 2.77 mmol) was added. The mixture was concentrated under high vacuum. The residue was chromatographed [silica, hexanes/ethyl acetate (4:1)] to afford a pale orange oil (1.85 g, 36%): 1H NMR δ 2.86 (t, J=8.0 Hz, 2H), 4.11 (t, J=8.0 Hz, 1H), 5.02-5.12 (m, 2H), 5.83 (m, 1H), 6.08 (s, 2H), 6.15 (m, 2H), 6.65 (m, 2H), 7.83 (br s, 2H); 13C NMR δ 37.3, 38.7, 105.6, 107.6, 116.3, 117.1, 132.8, 136.2; FABMS obsd 187.1230, calcd 187.1235 [(M+H)+], (M=C12H14N2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c2cc1OC
Yield: 26.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) was reacted with 4-tert-butylphenyl isocyanate (54 uL, 0.3 mmol) as described in Example 173 to give 1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (40 mg, 0.08 mmol, 27%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 7.84 (s, 1H), 7.51 (d, 1H), 7.45-7.20 (m, 8H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].S(OC)(O[CH3:26])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[N:6]([CH3:26])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.07 g (1.75 mmol)) in DMF (2.0 ml), 2′,4′-dichloro-p-toluenesulfonanilide (0.50 g (1.58 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.17 ml (1.80 mmol)) was added dropwise. After 15 hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crystals separated were filtered and washed with diisopropyl ether to give 0.38 g (73%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1)=[O:11].[NH2:26][OH:27].CO.[OH-].[Na+]>C1COCC1.O>[OH:27][NH:26][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([S:15][CH2:14][CH2:13][NH:12][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(SCCNC(=O)c2cc3ccccc3o2)cc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccc(SCCNC(=O)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-{2-[(benzofuran-2-yl-carbonyl)amino]ethylsulfanyl}-benzoate in THF (2 ml) was added a solution of 50% hydroxylamine in water (4 ml). Methanol (2 ml) and 0.1 M NaOH (0.1 ml) were added. The reaction mixture was stirred for three days at room temperature. The solvents were evaporated and the residue was crystallized from dichloromethane/ethyl acetate, to give the title compound (46 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([NH2:64])[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CO[CH:68]1[CH:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[N:86])=[CH:81][CH:80]=3)=[CH:75][CH:74]=2)[CH2:71][CH:70](OC)O1>ClCCCl>[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([N:64]1[CH:70]=[CH:71][C:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:80]=[CH:81][C:82]([C:85]#[N:86])=[CH:83][CH:84]=3)=[CH:75][CH:74]=2)=[CH:68]1)[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Agent: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Temperature: 87.5 °C
Yield: 39.1 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluroacetate salt, crude 3(R)-amino-N-(l(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(a); 0.876 mmol) was condensed with 4'-(2,5-dimethoxytetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (326 mg, 1.05 mmol) in 1,2-dichloroethane (5 mL). The solution was heated at 85-90° C. for 5 hours, allowed to cool, and evaporated to give a brown oil which was purified via flash column chromatography with 1% HOAc/30% d, EtOAc/hex as eluant. HOAc was removed via azeotrope with n-heptane layers to provide 200 mg (39%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow powder, mp 149-50° C. 1H NMR (CDCl3): ∂ 7.74 (s, 4H), 7.59 (d, 4H, J=4.1 Hz), 7.32-7.18 (m, 10H), 7.05 (bm, 2H), 6.94 (t, 1H, J=2.2 Hz), 6.64 (t, 1H, 2.5 Hz), 6.58 (bm, 1H), 5.48 (d, 1H, J=7.8 Hz), 5.10 (d, 2H, J=3.1 Hz), 5.00 (dd, 1H, J=5.0, 9.3 Hz), 4.46-4.32 (m, 2H), 4.22-4.12 (m, 1H), 3.41 (dd, 1H, J=5.3, 17.1 Hz), 3.04 (dd, 1H, J=9.1, 17.1 Hz), 2.70-2.63 (m, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm-1. HRFABMS: Calculated for C37H33N3O4Cs (MH+Cs+): 716.1525. Found: 716.1503. Anal. Calculated for C37H33N3O4.0.4 CH2Cl2 : C, 72.73; H, 5.52; N, 6.80. Found: C, 72.67, H, 5.53; N, 6.81.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3,4-Dichloroaniline (213.8 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 413 g (92%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:23][CH:25]4[O:27][CH2:26]4)=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(O)cc2C1=O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(OCC3CO3)cc2C1=O
Yield: 94 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (2.9 g), epichlorohydrin (10 ml) and potassium carbonate (2 g) was heated under reflux in acetone (10 ml) for 24 hr. The hot mixture was filtered and evaporation of the filtrate in vacuo gave 4-(3,4-dichlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone as a yellow gum (3.2 g, 94%).
Reaction SMILES: C(C(N1CCNCC1)C1C=CC(OC)=CC=1)#N.CO.[Cl:20]C(OCC)=O.[C:26]([CH:28]([N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)#[N:27]>C1C=CC=CC=1>[ClH:20].[C:26]([CH:28]([N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1)[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)#[N:27]
Reactant: CCOC(=O)Cl
Agent: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)cc2)CC1
Agent: COc1ccc(C(C#N)N2CCNCC2)cc1
Solvent: c1ccccc1
Solvent: CO
Product: Cl
Reaction time: 2 h

Procedure:
In a 100-ml. three necked flask was placed 11.5 g. of N-(α-cyano-4-methoxybenzyl)piperazine and 40 ml. of methanol to obtain a homogenous solution. To the resulting solution was added dropwise 5.96 g. of ethyl chloroformate over a period of about 70 minutes with stirring while the temperature was kept at about 20°C. After dropping, the internal temperature was raised to 40° to 45°C., and then the mixture was further stirred for 2 hours. The solution was concentrated under reduced pressure and 500 ml. of water was added thereto. This solution was made alkaline with the aid of sodium carbonate with cooling and extracted with benzene. The benzene layer was washed with dilute hydrochloric acid and water, and dried over sodium sulfate. The solvent was distilled off to afford 9.7 g. of N-(α-cyano-4-methoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in benzene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from acetone afforded N-(α-cyano-4-methoxybenzyl)-N' -ethoxycarbonylpiperazine hydrochloride having a melting point of 170°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22]C=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[CH:25]=[CH:24][S:48][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3sccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2sccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.39, 7.12, 6.99, 5.45, 4.64, 2.90, 2.65, 2.51, 2.20, 1.99, 1.27, 1.20; 13C NMR (100 MHz, CDCl3) δ 151.51, 150.78, 140.47, 139.15, 137.82, 137.21, 135.35, 134.47, 132.93, 128.78, 127.51, 127.37, 123.01, 117.71, 46.74, 29.97, 27.62, 26.36, 25.53, 21.37,12.32, 11.63; HRMS (FAB) calcd for C22H23Cl2N3S+H 432.1068, found 432.1073.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.C([Mg]Br)(C)C.CN([CH:19]=[O:20])C.O>C1COCC1>[N:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([CH:19]=[O:20])[CH:3]=[CH:4][C:5]=12
Reactant: Ic1ccc2ncnn2c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2ncnn2c1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
To a solution of 6-iodo-[1,2,4]triazolo[1,5-a]pyridine (5.0 g, 20 mmol; prepared from 2-amino-5-iodopyridine (Aldrich-Sigma, St. Louis, Mo.) according to WO 01/62756) in anhydrous THF (300 mL) at 0° C. was slowly added a solution of isopropylmagnesium bromide in THF (1 M, 31 mL, 31 mmol). The resulting milky suspension was stirred at 0° C. After an hour, DMF (6 mL, 50 mmol) was added to the suspension at 0° C. and the suspension was allowed to warm up to room temperature and stirred for 4 additional hours. 100 mL of water was then added at room temperature and stirred for 1 hour. The resulting mixture was extracted with diethylether and washed with saturated Na2CO3. The extracts were dried over MgSO4 and concentrated. The residue was purified on a short silica gel cake with EtOAc to give [1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde as a light yellow solid (3 g, 100%). ESP+ m/e 148.0. 1H NMR (CDCl3, 300 MHz), δ 10.03 (s, 1H), 9.10 (s, 1H), 8.49 (s, 1H), 8.02 (d, 1H), 7.82 (d, 1H).
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[C:26]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([CH3:32])[CH2:25][CH2:24]2.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)([OH:31])[C:26]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([CH3:32])[CH2:25][CH2:24]2
Reactant: C#CCCCCOC1CCCCO1
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2(C)CCc3cc(OC)ccc3C2(O)C#CCCCCOC2CCCCO2)cc1
Reaction time: 0.5 h

Procedure:
n-Butyllithium (8.4 ml. of a 1.55 molar solution in hexane) was added to a solution of 6-tetrahydropyranyloxyhex-1-yne (2.25 g.) in tetrahydrofuran (25 ml.) at 10° C., the mixture was allowed to warm up to laboratory temperature and was stirred at that temperature for 30 minutes, and was then recooled to 10° C. A solution of 3,4-dihydro-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalen-1(2H)-one (2.0 g.) in tetrahydrofuran (20 ml.) was added dropwise and the mixture was allowed to warm up to laboratory temperature and stirred at that temperature for 30 minutes. Saturated aqueous ammonium chloride solution (50 ml.) was added and the mixture was extracted with ethyl acetate. The extract was dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 3:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. The product was crystallised from ethanol and there was thus obtained, as a mixture of isomers, 6-methoxy-2-p-methoxyphenyl-2-methyl-1-(6-tetrahydropyranyloxyhex-1-ynyl)-1,2,3,4-tetrahydronaphth-1-ol, m.p. 80°-82° C.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=CO[CH:8]=2)=[CH:3][CH:2]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1C=C(I)C=[N:35]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2C=CC=CC=2)C=CC(B(O)O)=CC=1>>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=2)[CH:11]=[N:35]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(I)cn1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(-c2ccc(-c3ccccc3)cc2)cn1
Yield: 39 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-iodopyrazol-1-yl)-ethanone was coupled to 4-biphenylboronic acid to provide in 39% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-biphenyl-4-yl-pyrazol-1-yl)-ethanone as a white solid, mp 150-1° C. 1H NMR: δ 7.83 (s, 1H), 7.68 (s, 1H), 7.62-7.52 (m, 6H), 7.47-7.28 (m, 8H), 4.83, 4.38 (AB quartet, 2H, J=15.6 Hz), 4.22-4.18 (m, 1H), 3.94 (m, 2H), 3.09 (dd, 1H, J=6.4, 13.0 Hz), 2.97 (dd, 1H, J=8.5, 13.2 Hz), 1.79 (s, 3H), 1.55 (s, 3H). Anal. Calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.31. Found: C, 77.04; H, 6.52; N, 9.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:25][CH:26]=[CH2:27]>C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:27][CH:26]=[CH2:25])[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: C=CCBr
Solvent: c1ccccc1
Product: C=CCN1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cl

Procedure:
To a stirring solution of 5 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 3.8 parts of N-N-diethylethanamine in 200 parts of benzene are added portionwise 5 parts of 3-bromo-1-propene. After the addition is complete, the whole is heated for 21 hours at a temperature between 50°-60° C. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, dried over potassium carbonate and evaporated. The oily residue is converted into the hydrochloride salt in 1,1'-oxybisethane and 2-propanone, yielding 4 parts of N-(4-chlorophenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamide hydrochloride; mp. 225.5° C.