Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH3:22].O>CC(C)=O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH3:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a stirred mixture of 1-(4-bromophenyl)piperazine (4.82 g, 20 mmol) and K2CO3 (5.44 g, 40 mmol) in acetone (200 mL) was added iodoethane (2.58 mL, 32 mmol) dropwise over 1 min. After addition, the resulting mixture was stirred at rt for 24 h. The resulting precipitate was filtered off and rinsed with EtOAc (2×30 mL). The filtrate was concentrated to dryness to give a white solid which was treated with H2O (60 mL). Extraction with EtOAc (100 mL+60 mL) followed by concentration gave the crude title compound as a white solid. Trituration with MeOH (40 mL) gave first crop as a white solid (1.30 g). The mother liquor was concentrated to dryness and the trituration was repeated with MeOH, hexane and H2O to give additional 3.60 g as white solid. Total: 4.90 g (91%). 1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J=7.6 Hz, 2H), 6.87 (d, J=7.6 Hz, 2H), 3.13-3.03 (m, 4H), 2.49-2.40 (m, 4H, partially overlapping with DMSO signal), 2.34 (q, J=6.8 Hz, 2H), 1.01 (t, J=6.8 Hz, 3H); MS ESI 269.0[M+H]+, calcd. for [C12H17BrN2+H]+ 269.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47]O.N1C=CC=CC=1.P(Br)(Br)[Br:56]>CCOCC.C(OCC)(=O)C>[CH2:31]([O:30][C@H:11]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:47][Br:56])[CH:4]=2)[O:9][C@H:10]1[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: Clc1ccc(C2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-5-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy-methyl) tetrahydro-2H-pyran-2-yl)phenyl)methanol (compound 5, 130 g, 195 mmol) from Step 6 in ether (600 mL) at 0° C. was added pyridine (0.79 mL, 9.8 mmol) and phosphorus tribromide (6.4 mL, 68 mmol). The reaction was allowed to slowly warm to room temperature over 15 h and refluxed 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water then brine. The organic extract was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])(=O)=O)=CC=1.C(Cl)[Cl:24].[C:26](=[O:28])=O>[OH-].[Na+]>[Cl:24][C:19]1[CH:18]=[CH:17][C:16]([O:28][CH3:26])=[C:15]2[C:20]=1[C:12](=[N+:11]=[N-:10])[C:13](=[O:21])[NH:14]2
Reactant: Cc1ccc(S(=O)(=O)NN=C2C(=O)Nc3ccccc32)cc1
Reactant: ClCCl
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)c2c1NC(=O)C2=[N+]=[N-]

Procedure:
30.0 g (0.079 mole) of the isatin-3-p-toluenesulfonylhydrazone (prepared in part A) is suspended in 900 ml 0.2 N NaOH and heated slightly for ~30 minutes. The mixture is stirred for 22 hours at room temperature with a layer of methylene chloride (300 ml). The methylene chloride is stripped off and the aqueous phase saturated with CO2 (dry ice used). The light peach-colored precipitates are filtered off, washed with a small amount of H2O and dried in vacuo at 45° for 11/2 hours to give 19.2 g of title compound (Theor. yield = 17.7 g). The crude product is taken up in 1.8 1. CH3OH and the clear light red solution concentrated down to a volume of 500 ml, cooled, filtered and dried overnight in vacuo at room temperature. Yield of title compound is 15.2 g, m.p. 206°-207°, light orange crystals.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:5]1.O=S(Cl)[Cl:17]>>[Cl:17][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:5]1
Reactant: O=S(Cl)Cl
Reactant: OCCn1ccc(-c2ccncc2)n1
Product: ClCCn1ccc(-c2ccncc2)n1

Procedure:
C] 1-(2-Chloroethyl)-3-(4-pyridinyl)-1H-pyrazole was prepared according to example 14C from 1-(2-hydroxyethyl)-3-(4-pyridinyl)-1H-pyrazole by treatment with SOCl2. MS (EI): 207.1 (M+). 1H-NMR (DMSO-d6): 4,06 (t, 2H), 4.53 (t, 2H), 6.92 (d, 1H), 7.76 (m, 2H), 7.93 (d, 1H), 8.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].B.C1COCC1.Cl.CO>C1COCC1.O1CCOCC1>[NH2:9][CH2:8][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]2[CH:18]=[CH:19][N:20]=[C:3]2[C:2]=1[NH2:1]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: NCc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N
Temperature: 0 °C
Yield: 60.9 %

Procedure:
To a solution of 8-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (32.5 mg, 0.11 mmol) in THF (1 mL) was added a BH3.THF complex (1.0 M solution in THF, 0.43 mL, 0.43 mmol) followed by 4 M HCl in dioxane (2 drops). The reaction mixture was stirred and refluxed for 4 h, then cooled to 0° C. (ice bath) and poured into MeOH. The mixture was concentrated under vacuum, then the remaining residue was dissolved in TFA, evaporated to dryness and purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 35.7 mg, 0.067 mmol, 62%). MS: 307 [M+1]+; HPLC: AtRet=0.99.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:14]4[CH2:29][CH:30]5[NH:34][CH:33]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH2:20][OH:21])[C:14]2[CH2:29][CH:30]4[NH:34][CH:33]([C:13]3=2)[CH2:32][CH2:31]4)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2CCO[Si](C)(C)C(C)(C)C)CC2CCC1N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)c1c(n2CCO)CC2CCC1N2
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of the product of step A (110 mg, 0.30 mmol) in dichloromethane at 0° C. was added trifluoroacetic acid (0.57 ml, 7.5 mmol) and the reaction was stirred overnight. The reaction mixture was made basic with saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was crystallized from dichloromethane to give 2-phenylsulfonyl-5-(2-hydroxy)ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (100 mg, 87%) as a white crystalline solid: 1H NMR (CDCl3, 300 MHz), δ 8.27 (s, 1H), 7.93-7.96 (m, 2H), 7.71 (dd, J=9.0, 1.2 Hz, 1H), 7.52-7.62 (m, 4H), 5.29-5.31 (m, 1H), 4.53 (br s, 1H), 4.24 (t, J=5.1 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 3.54 (dd, J=17.4, 4.5 Hz, 1H), 3.12 (d, J=20.7 Hz, 1H), 2.23-2.46 (m, 3H), 1.93-1.97 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[C:8]1([CH3:21])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([NH:19]O)(=[O:18])=[O:17].CC[O:24]CC>ClCCl>[C:8]1([CH3:21])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([O-:24])(=[O:18])=[O:17].[NH2:19][N+:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1
Reactant: Cc1ncsc1C
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1sc[n+](N)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An ice cold solution of the 4,5-dimethyl thiazole (2,26 g, 20 mmol) in dry dichloromethane (15 ml) was treated dropwise with a solution of o-mesitylenesulfonylhydroxylamine (4.3 g, 20 mmol) in dry dichloromethane (15 ml). After stirring for 2 hours at room temperature, anhydrous ether (10 ml) was added. On cooling, colorless needles of the title product, 3-amino-4,5-dimethyl-thiazolium mesitylenesulfonate, separated (3.48 g), m.p. 165-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10]O)=[NH:9])=[N:6][CH:7]=1.[C:12]([O:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13].[H][H]>C(O)(=O)C.[Pd]>[C:12]([OH:15])(=[O:14])[CH3:13].[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:18])[CH3:17])=[CH:3][CH:4]=1)(=[NH:9])[NH2:10]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: N=C(NO)c1ccc(N)cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=N)N)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 1 (0.2 g, 1.32 mmol) in acetic acid was added acetic anhydride (0.202 g, 1.98 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 5 minutes. To the reaction mixture, 10% Pd/C (0.028 g) was added and shaken with hydrogen on Parr hydrogenation apparatus at a pressure of about 15 psi for a period of 4 hours. The reaction mixture was filtered through celite and the filter pad was washed with glacial acetic acid (15 mL). The filtrate was combined and acid removed under reduced pressure. The traces of acid were removed by using petroleum ether and the solid obtained was purified by column chromatography using silica gel and 10% methanol/chloroform as eluent to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]([N:20]=[C:21]=S)=[O:19])[CH3:16].[CH2:23]([NH:26][CH2:27][CH2:28]C)[CH2:24]C>CN(C=O)C>[CH:9]1([NH:8][C:3]2[C:2]([N:1]=[C:21]([NH:20][C:18](=[O:19])[O:17][CH2:15][CH3:16])[N:26]([CH2:27][CH3:28])[CH2:23][CH3:24])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cccnc1NC1CCCCC1
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCOC(=O)NC(=Nc1cccnc1NC1CCCCC1)N(CC)CC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.02 mol (3.82 g) of 3-amino-2-cyclohexylaminopyridine from Preparation 1 and 0.02 mol of ethoxycarbonyl isothiocyanate is stirred in 50 ml of DMF at ambient temperature for 3 hours. The solution is then cooled to 0° C., and 0.05 mol of dipropylamine and then 0.02 mol of mercuric chloride are added in succession. After 15 minutes, the ice bath is removed and the solution is stirred at ambient temperature for 4 hours. After diluting the solution with 100 ml of ethyl acetate, filtration is carried out over Celite and the solvents are evaporated off under reduced pressure. The resulting crude product is then recrystallised from acetonitrile.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N1CC[O:33]CC1)C.ClC(OCC(C)C)=O.N1CCCC(C(OCC)=O)C1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:33])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CCOC(=O)C1CCCNC1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 161.1 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (266 mg, 0.71 mmol, 1.0 eq), N-ethylmorpholine (135 uL, 1.06 mmol, 1.5 eq) in acetonitrile (5.0 mL) was treated with isobutyl chloroformate (101 uL, 0.78 mmol, 1.1 eq) followed by ethyl nipecotate (220 uL, 1.40 mmol, 2.0 eq). Purification by flash chromatography provided 150 mg (41%) of L-isoleucine, N-[1-[2-[N-(piperidine-3-carboxylic acid ethyl ester)]-2-oxoethyl]-L-prolyl] benzylamide as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([CH3:15])[NH:13][CH3:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](Cl)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([N:13]([CH3:14])[C:27](=[O:28])[CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH3:15]
Reactant: CNC(C)CCc1cc(OC)ccc1I
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(I)c(CCC(C)N(C)C(=O)Cc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 17.87 g (0.056 mole) of 2-iodo-5-methoxy-N,alphadimethylbenzenepropanamine in 58 ml of dry methylene chloride was added dropwise to a cooled (5° C.) solution of 3,4-dimethoxyphenylacetyl chloride in 68 ml of dry methylene chloride over a period of five minutes while stirring under an atmosphere of nitrogen. After about two minutes of stirring, 5.67 g (0.056 mole) of triethylamine was added followed by an additional 20 ml of dry methylene chloride. The reaction mixture was allowed to warm to room temperature while stirring overnight. An additional 80 ml of methylene chloride was added and the mixture washed successively with 200 ml of water, 300 ml of 5% hydrochloric acid, and 200 ml of sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 27.5 g (99%) of N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-3,4-dimethoxy-N-methylbenzeneacetamide as an orange gum, MS (high resolution):
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(#N)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)cc1
Reactant: CNCc1ccc2ccccc2n1
Solvent: CC#N
Product: CN(Cc1ccc2ccccc2n1)C[C@@H](O)COc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-(Methylaminomethyl)quinoline (5.57 g, 32.41 mmol) in acetonitrile (30 mL) was added to a stirring solution of (R)-(-)-2-[(4-nitrophenoxy)methyl]oxirane (6.32 g, 32.41 mmol) in acetonitrile (90 mL) and the mixture was stirred 18 hours at 60° C., then 48 hours at 20° C. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate/brine. The organic layer was dried, decolorized, and concentrated to afford crude product which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (240 mg, 0.834 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (153 mg, 50.2%) as a solid.
Reaction SMILES: [C-]#[C-].[Li+:3].[Li+].C[O:6]CCl.BrC[C:11]1[C:12]([O:16]C)=NO[CH:15]=1.[C:18]1(C(C2C=CC=CC=2)OC2C(CI)=NSN=2)C=CC=C[CH:19]=1.C(=O)=O>O1CCCC1>[C:12]([OH:16])(=[O:6])[C:11]#[CH:15].[C-:18]#[C-:19].[Li+:3].[Li+:3]
Reactant: COc1nocc1CBr
Reactant: ICc1nsnc1OC(c1ccccc1)c1ccccc1
Reactant: COCCl
Agent: O=C=O
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CC(=O)O

Procedure:
Dibromoolefin intermediate XIX is then converted to ethynyl intermediate XX. Treatment of the dibromoolefin intermediate with about two equivalents of n-butyllithium produces the lithium acetylide XX, wherein R13 is Li. This transformation is typically carried out in a polar organic solvent, such as tetrahydrofuran, at a temperature of about -78° C. to about 25° C. The lithium acetylide is reacted with electrophiles, such as methoxymethyl chloride, bromomethyl-3-methoxyisoxazole, 3-diphenylmethoxy-4-iodomethyl-1,2,5-thiadiazole, carbon dioxide, tetrazole disulfide, and the like, to prepare the formula I compounds. In a typical example, the lithium acetylide is treated with solid CO2 at a temperature of about -78° C. to about -60° C. to produce propargylic acid intermediate XX wherein R13 is CO2H. This compound may be further modified as described herein.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:42][C:16]2[N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:18](=[O:26])[N:19]([CH:22]([CH3:25])[CH2:23][OH:24])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:42][C:16]2[N:17]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:18](=[O:26])[N:19]([CH:22]([CH3:25])[CH:23]=[O:24])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12]
Reactant: CCc1cc2c(=O)n(C(C)CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(C(C)C=O)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a mixture of oxalylchloride (0.43 mL) and methylene chloride (10 mL) were added a solution (10 mL) of dimethyl sulfoxide (0.35 mL) in methylene chloride and a solution (10 mL) of 4′-{[6-ethyl-3-(2-hydroxy-1-methylethyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2 g) in methylene chloride at −78° C., and the mixture was stirred at the same temperature for 15 min. Triethylamine (3.14 mL) was added, and the mixture was allowed to warm to room temperature. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.7 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11][OH:12])[C:7]([O:9][CH3:10])=[O:8].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>C(O)C>[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[N:1][C:2]2[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=2[CH2:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:6]([CH2:11][OH:12])[C:7]([O:9][CH3:10])=[O:8])=[CH:30][CH:29]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: COC(=O)C(CO)N(Cc1ccccc1N=Cc1ccncc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 65.2 %

Procedure:
A mixture of 0.50 g (1.268 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxy-benzenesulfonyl)amino]-3-hydroxypropionate and 1.268 mmol of 4-pyridine-carboxaldehyde in 7 ml of anhydrous ethanol was refluxed for 1.5 hours and the mixture concentrated under vacuum to dryness. To the residue was added H2O and ethyl acetate. The ethyl acetate layer was separated and concentrated to dryness under vacuum. The solid was purified by thick layer chromatography on silica gel with hexane-ethyl acetate as solvent to give 0.40 g of solid product (plus a small amount of starting material). Anal. for C24H25N3O6S: Calc'd: C, 59.6; H, 5.2; N, 8.7; Found: C, 57.6; H, 5.7; N, 7.4.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1>C(OCC)(=O)C.[Pd].ClCCl.CCCCCC>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution hexane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1
Reactant: Clc1cnccc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cc(C(F)(F)F)nc(SCc2ccncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3-chloropyridine hydrobromide (7.2 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (922 mg, 4.7 mmol) in absolute ethanol (40 mL) was added triethylamine (4.0 mL, 28.7 mmol). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. Diethyl ether (2×50 mL) was used to wash the recovered solid. The solid material was removed by filtration. The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×25 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×30 mL), diethyl ether (1×30 mL), and hexanes (2×30 mL), and was dried in vacuo to afford 2-{[(3-chloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (822 mg, 54%); 1H NMR (500 MHz, DMSO-d6): δ 4.50 (s, 2H), 6.66 (s, 1H), 7.58 (d, 1H, J=4.9 Hz), 8.47 (d, 1H, J=4.9 Hz), 8.64 (s, 1H); M+322.