Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+:5].[CH:6]1([CH2:12]Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O>[Na+:5].[CH:6]1([CH2:12][S:1]([O-:3])(=[O:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S([O-])O
Reactant: BrCC1CCCCC1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC1CCCCC1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
To a solution of sodium bisulfite (32 g, 307 mmole) in H2O (200 mL) was added cyclohexylmethyl bromide (21 mL, 150 mmole). The mixture was then stirred vigorously while heated at reflux for 48 hours. Upon cooling to room temperature, a white precipitate formed. The precipitate was collected on a Buchner funnel and washed with diethyl ether to wash away residual cyclohexylmethyl bromide. The white plate-like solid was dried under high vacuum overnight to provide 11.8 g (39%) of the title compound which had a m.p. >400° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=C=O)[CH:13]=[C:14]([CH3:17])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si]([O:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40])(C(C)(C)C)(C)C.O.[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:36][NH:35][C:33](=[O:34])[C:32]3[CH:37]=[CH:38][C:29]([CH2:28][OH:27])=[C:30]([N+:39]([O-:41])=[O:40])[CH:31]=3)[CH3:43])[C:15]=2[OH:16])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CS(=C=O)C(c2ccc(C(C)(C)C)cc2)=C1O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: CC(=NNC(=O)c1ccc(CO)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 248.1 %

Procedure:
A solution of 2-(4-tert-butylphenyl)-3-hydroxy-4-methyl-carbonylthiophene (27.8 mg, 0.10 mmol), 4-(tert-butyl-dimethylsilanyloxymethyl)-3-nitrobenzoic acid hydrazide (34.9 mg, 0.11 mmol) and p-toluenesulfonic acid monohydrate (5.7 mg, 0.03 mmol) in isopropanol (1.0 mL) was stirred at 95° C. for 7 hours. The precipitated solid was collected by filtration and dried by means of a vacuum pump to give the desired product as yellow solid (34.8 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.BrC[CH2:18][OH:19].[C:20](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:20])[CH2:15][CH2:18][OH:19])[CH2:6]2
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Reactant: OCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCO)C2
Reaction time: 8 h

Procedure:
At ambient temperature, 1.04 g (5 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}methylamine, 0.44 mL (6 mmol/1.2 eq.) of 2-bromoethanol and 2.07 g (15 mmol/3 eq.) of potassium carbonate are mixed into 10 mL of acetonitrile. Refluxing is carried out overnight, followed by drying. The residue is taken up in dichloromethane, washed with water and dried over magnesium sulphate to yield, after concentration, the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])=[CH:6][C:5]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[C:4]([F:34])[CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])=[CH:6][C:5]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[NH:24][C:23]2=[O:33])=[C:4]([F:34])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(Cl)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A suspension of 10% Pd/C and 3-[4-chloro-2-fluoro-5-(4-nitro-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.0 g) in ethyl acetate (100 ml) was stirred overnight under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrate concentrated. The resulting oil was chromatographed on silica gel eluting with ethyl acetate:hexane, 1:0.8.3-[4-Chloro-2-fluoro-5-(4-amino-2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-24) was isolated as an amorphous solid (33 g).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])=[N:4][CH:3]=1.C([O:30][C:31](=[O:34])[CH2:32][NH2:33])C.BrC1N(C2C3C(=CC=CC=3)C(C#N)=CC=2)C(SCC(O)=O)=NC=1.NCC(NCC(OCC)=O)=O>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([NH:33][CH2:32][C:31]([OH:34])=[O:30])=[O:27])=[O:22])=[N:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)O)c2ccccc12
Agent: CCOC(=O)CNC(=O)CN
Agent: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)NCC(=O)NCC(=O)O)c2ccccc12

Procedure:
2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetamido)acetic acid is prepared via either of the two routes shown below. In the first, 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetic acid (see eg 3) is coupled with glycine ethyl ester and then hydrolyzed to the acid. In the second, 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid (see eg 1) is coupled with NH2-Gly-Gly-OEt, which is then hydrolyzed to the acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)c1ccccc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Yield: 76 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-bromopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (microwave—120° C., 10 minutes) to afford 2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 76% yield. MS: 342.96 (M+H); 1H NMR (d6-dmso): δ 11.96 (s, 1H), δ 8.85 (br s, 1H), δ 8.57 (s, 1H), δ 8.47 (d, J=9 Hz, 1H), δ 7.79 (d, J=8 Hz, 1H), δ 7.57 (t, J=8 Hz, 1H), δ 7.22 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(N(CC)CC)C>>[CH2:18]([CH:17]([CH2:20][CH3:21])[CH2:16][NH:15][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:19]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCC(CC)CN
Solvent: CCN(CC)CC
Product: CCC(CC)CNc1nc(SC)ncc1C(=O)OC
Yield: 102.6 %

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (0.40 g, 1.72 mmol) was reacted with 1-amino-2-ethyl butane (0.175 g, 1.72 mmol) and triethylamine (0.60 mL, 4.32 mmol) at ambient temperature for 18 hours. The reaction was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and the concentrated to give the title compound (0.50 g, 98%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][C:17]([CH:20]([CH2:22][OH:23])[OH:21])([OH:19])[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:24][C:25]([CH3:27])=O>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:24][C:25]1([CH3:27])[O:21][CH:20]([C:17]([OH:19])([CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:18])[CH2:22][O:23]1
Reactant: CC(C)=O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C(O)CO
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)(O)C1COC(C)(C)O1

Procedure:
One g of phytantriol (3.0 mmol, Sigma-Aldrich) was refluxed using deanstock apparatus for 15 hr in 25 ml of acetone solution with toluene sulfonic acid as catalyst. After the completion of the reaction, the acetone solvent was removed under reduced pressure and the resultant was extracted with chloroform solution. The extract was washed with saturated sodium bicarbonate solution and was again washed with saline to obtain 0.3 g of (2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-6,10,14-trimethyl-pentadecan-2-ol) of which 1- and 2-positions were protected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]([N:18]([CH:34]2[CH2:36][CH2:35]2)[C:19]([C@@H:21]2[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[O:20])[CH3:17])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:16]([N:18]([CH:34]2[CH2:36][CH2:35]2)[C:19]([C@@H:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[O:20])[CH3:17])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]=1[O:8][CH3:9].[Br:1][C:2]1[CH:3]=[C:4]([C@@H:16]([N:18]([CH:34]2[CH2:36][CH2:35]2)[C:19]([C@@H:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[O:20])[CH3:17])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:7]=1[O:8][CH3:9]
Reactant: COCCCOc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc(Br)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc([C@@H](C)N(C(=O)[C@H]2CNCCO2)C2CC2)cc(Br)c1OC
Product: COCCCOc1cc([C@H](C)N(C(=O)[C@H]2CNCCO2)C2CC2)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2R)-2-{[{1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)-phenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholine-4-carboxylate (135 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the resulting residue was added chloroform, and the mixture was filtered through (Bond-Elute: registered trademark) (NH2). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate/methanol/ammonia water=200/10/1) to give (2R)-N-{(1R)-1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)phenyl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(5-1)] (53.7 mg) and (2R)-N-{(1S)-1-[3-bromo-4-methoxy-5-(3-methoxypropoxy)phenyl]ethyl}-N-cyclopropylmorpholine-2-carboxamide [Ex(5-2)] (30.5 mg) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]>C(Cl)Cl.C(#N)C>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:12][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C:23]#[C:24][CH3:25]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred suspension of methyl-1-amino-1-cyclohexane carboxylate hydrochloride (10 g, 51.7 mmol) and N,N-diisopropylethylamine in methylene chloride (200 mL) and acetonitrile (50 mL), 4-but-2-ynyloxy-benzenesulfonyl chloride (14.0 g, 56.8 mmol) was slowly added at room temperature. The reaction mixture was stirred for 16 hrs and evaporated to dryness. It was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. The chloroform layer was filtered and concentrated. The product was crystallized from a mixture acetone:hexane 1:10 to give methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexanecarboxylate as white crystals, 12.5 g. (66%), mp 118-2° C. Electrospray Mass Spec 366 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O[N:29]1C2C=CC=CC=2N=N1.CN1CCOCC1.COC1C=CC(CON)=CC=1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:14]([CH:18]([CH3:19])[CH3:20])[C:15]([NH2:29])=[O:17])[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccc(CON)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)C(C(N)=O)C(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (2.41 g, 5.82 mmol), 1-hydroxybenzotriazole (0.786 g, 5.82 mmol), 4-methyl-morpholine (1.9 mL, 17.46 mmol), and O-(4-methoxybenzyl)hydroxylamine (1.78 g, 11.63 mmol) (prepared according to Pol. J. Chem. 55, 1163°-1167 (1981 )) are dissolved in methylene chloride (55 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.45 g, 7.57 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate followed by 5% methanol/ethyl acetate) to give N-(4-methoxybenzyloxy)-2CR)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide, m.p. 45°-53° C.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Yield: 64.9 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DIPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1 Step C, except for the purification method. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H) 3.88-4.16 (m, 5H), 4.73 (s, 1H), 4.85 (m, 1H) 5.26-5.39 (m, 1H) 6.90 (bs, 1H), 7.06(m, 2H), 7.24(m, 1H). ESI-MS 489 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[SH:17]>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Sc1cc(Cl)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1cc(Cl)ccc1Cl
Yield: 85.6 %

Procedure:
The procedure of Example 13 was repeated, reacting a slurry of N-chlorosuccinimide (3.72 g., 27.9 mmoles) in 50 ml. of carbon tetrachloride with 2,5-dichlorothiophenol (5.0 g., 27.9 mmoles) in 25 ml. of carbon tetrachloride. 2,5-Dichlorobenzenesulfenyl chloride (5.1 g.) was isolated as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min) Title compound isolated (70 mg, 47%) as an off-white solid. MP 233-234, LCMS 492.27 (M+H), HPLC purity 98%, 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, 7.9 Hz, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30-7.21 (m, 2H), 7.18-7.09 (m, 3H), 6.08 (bt, J=5.1 Hz, 1H), 4.93 (s, 2H), 4.88-4.82 (m, 1H), 4.39-4.33 (m, 1H), 3.83-3.78 (m, 1H), 3.82-3.75 (m, 1H), 3.08-3.02 (m, 1H), 2.81-2.74 (m, 1H), 2.64-2.59 (m, 1H), 1.83 (s, 3H).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[O-]CC.[Na+].[CH2:14](Cl)[CH:15]=[CH2:16]>C(O)C>[CH2:1]([P:3]([CH:14]=[CH:15][CH3:16])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CCCl
Reactant: CCCCOP([O-])CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC=CP(=O)(CC)OCCCC
Yield: 26 %

Procedure:
At room temperature, a three-neck flask equipped with stirrer and high-performance condenser is initially charged with 400 g of ethanol and this initial charge is devolatilized by stirring and passing nitrogen through it. Then, under nitrogen, 30 g (0.2 mol) of butyl ethylphosphonite (produced as in Example 3) are added, followed by the dropwise addition of initially 14.5 g (0.25 mol) of sodium ethoxide in ethanol and thereafter 19.1 g (0.25 mol) of allyl chloride. Following a reaction time of 5 hours, the reaction solution is passed for purification through a column charged with Deloxan® THP II and the solvent is removed in vacuo. The product (butyl ethylpropenylphosphinate) is purified by column chromatography to obtain 9.9 g (26% of theory) of butyl ethylpropenylphosphinate as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6].[CH3:15][C:16]1[C:17](B(O)O)=[CH:18][C:19]2[C:20](C)([CH3:28])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1.[CH2:33](O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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.O>[F:12][C:11]([F:14])([F:13])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:17]1[C:16]([CH3:15])=[CH:25][C:24]2[C:23]([CH3:26])([CH3:27])[CH2:22][CH:21]([CH3:33])[CH:20]([CH3:28])[C:19]=2[CH:18]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CCO
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)C(C)C(C)CC2(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 3-bromo-4-trifluoromethoxybenzaldehyde (10.0 g, 37.2 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (11 g, 44.68 mmol, 1.2 eq) in a mixture of toluene (100 mL), ethanol (20 mL) and water (15 mL) was added potassium carbonate (10.28 g, 74.4 mmol, 2 eq). The solution was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol, 0.02 eq) was added and the mixture heated at reflux under argon for 22 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (silica: 70-230 mesh, 60A, 400 g, eluant: ethyl acetate/hexane, 5:95) to give 4-trifluoromethoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzaldehyde (11.1 g, 76%). 1H NMR (300 MHz; CDCl3) 1.25 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 7.06 (s, 1H); 7.18 (s, 1H); 7.48 (dd, J1=8.4 Hz, J2=1.5 Hz, 1H); 7.84 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1H), 9.91 (s, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]([CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[C:12]2=[S:26])=[CH:5][CH:4]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[NH:40]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]([CH:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17]4)[C:12]3=[S:26])=[CH:7][CH:8]=2)=[N:2][N:42]=[N:41]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(CCn2ccn(C3CCc4ccccc4C3)c2=S)cc1
Solvent: Cc1ccccc1C
Product: S=c1n(CCc2ccc(-c3nnn[nH]3)cc2)ccn1C1CCc2ccccc2C1
Temperature: 120 °C
Yield: 0 %

Procedure:
A mixture 3-[2-(4-cyanophenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 mmol), prepared as in Example 15, and tributyltin azide (1.39 g, 4.2 mmol) in 3 mL of xylene was heated at 120° C. under nitrogen for approximately 16 hours. The mixture was purified by chromatography on silica gel eluting with methylene chloride/methanol and the purified product was recrystallized from ethyl acetate/methanol to give 3-[2-(4(1H)-tetrazol-5-ylphenyl)ethyl]-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 nmol), m.p. 218°-220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br.O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:11](=[O:23])[C:10]=1[Br:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(Cn2ccc(OCc3ccccc3)cc2=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Reaction time: 2 h

Procedure:
The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15° C. Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was added dropwise. Contents were stirred 2 hours, coming to room temperature. Water (200 mL) was added and a light yellow solid was filtered. Mp 150.4-151.2° C. FABHRMS m/z 384.0599 (M+H, C20H19BrNO2 requires 384.0601). 1H NMR (CDCl3/300 MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m, 5H); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCCC1.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCc1cc(Cc2ccccc2)c(Br)cn1
Yield: 24.7 %

Procedure:
200 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine (Example 189a) and 10 mg of platinum (IV) oxide were added to 10 ml of methanol, 10 ml of tetrahydrofuran and 10 ml of ethyl acetate, followed by stirring at room temperature at normal pressure in a hydrogen atmosphere overnight. The catalyst was filtered off and the filtrate was evaporated, to give 50 mg of the target compound.