Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-methoxybenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.3 (s, 1H), 10.6 (s, 1H), 8.21 (d, 1H), 7.65 (m, 5H), 7.00 (m, 5H), 6.43 (d, 1H), 3.80 (s, 3H); LC-MS: 372 (MH+); HPLC RT: 5.45 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[O:25][C:26]([CH3:29])([CH3:28])[CH2:27]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)O1
Temperature: 75 °C
Yield: 95.1 %

Procedure:
Ethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate (54) (0.1095 g, 0.260 mmole) was dissolved in ethanol (5 mL). Potassium hydroxide (0.260 mL of a 3 M aqueous solution, 0.780 mmole) was added and the mixture was heated to 75° C. for 2.5 h. The solution was cooled to RT and concentrated. Water (25 mL) was added and the mixture was extracted with ether (10 mL). The organics were thrown out and the aqueous layer was treated with 1 N aqueous HCl to pH=3. The resulting mixture was extracted with methylene chloride (3×10 mL). The organics were dried (Na2SO4) and concentrated to provide 0.097 g (95%) of compound 55 as a pale yellow solid. 1H NMR (DMSO-d6): δ 12.33 (s, 1H), 9.34 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.44 (d, J=15.9 Hz, 1H), 2.14 (s, 2H), 2.11 (s, 2H), 1.11 (s, 6H), 1.10 (s, 6H). LRMS (ESI): m/z 391 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:18][CH:19]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 62.4 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.07 mL, 0.92 mmol), triethylamine (0.08 mL, 0.92 mmol), and 1-(4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B-1, 0.127 g, 0.31 mmol) provided 0.087 g of the title compound as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCOC
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(F)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl )methylamine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxyl]-butyl}-(2-methoxy-ethyl)-methyl-amine which was transferred into its salt by treatment with formic acid, MS: 389 (MH+).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C1(C)C=CC=CC=1.[C:13]([N:23]=[C:24]=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C>C(OCC)(=O)C>[C:13]([NH:23][C:24]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NC(=O)C=Cc1ccccc1
Reactant: N#CC1CN1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)C=Cc1ccccc1

Procedure:
A solution of 0.98 g. 2-cyanoaziridine in 20 ml. toluene is added dropwise, while stirring, at 20° to 30° C. to 2.5 g. cinnamoyl isocyanate dissolved in 20 ml. toluene. The resultant suspension is stirred for 1 hour at ambient temperature, then filtered off with suction and washed with toluene. The crystals obtained are triturated with anhydrous diethyl ether and dried for 1 hour at 50° C. in a vacuum to give 1.9 g. of crude product; m.p. 134°-136° C. This crude product is boiled with 50 ml. ethyl acetate for a short time, mixed with active charcoal and then filtered. The hot ethyl acetate filtrate is evaporated in a vacuum and the evaporation residue triturated with anhydrous diethyl ether. There is thus obtained 1.2 g. 1-(N-cinnamoyl-carbamoyl)-2-cyanoaziridine; m.p. 163°-164° C. The compound is practically insoluble in water but goes into solution upon the addition of excess 2 N aqueous sodium hydroxide solution.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N+:13]([C:16]1[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:19]1[S:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: O=[N+]([O-])c1ccc(C=NNC(=S)NC2CC3C=CC2C3)s1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and 5-nitrothiophene-2-carboxaldehyde (88 mg, 0.56 mmol) similar to Example 3 and isolated as an orange solid (67 mg, 37%). 1H NMR (CDCl3): 10.13 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=4.2 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.17 (d, J=4.2 Hz, 1H), 6.26-6.13 (m, 2H), 4.26-4.20 (m, 1H), 3.05 (s, 1H), 3.00 (s, 1H), 1.95-1.87 (m, 1H), 1.70 (d, J=9.0 Hz, 1H), 1.49 (d, J=9.0 Hz, 1H), 1.46-1.39 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4F)CC3)c(OC)nc2c1
Yield: 95 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.66 (s, 4H), 3.78 (s, 3H), 4.15 (s, 3H), 6.94-7.27 (m, 7H), 7.73-7.87 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:6]1([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC1C(=O)Nc2cc(Cl)ccc21
Product: CC1(Cc2ccccc2)C(=O)Nc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 6-chloro-3-methyl-1,3-dihydro-indol-2-one (700 mg) following similar methods to those described in Preparation 185 using benzyl bromide instead of iodomethane to give the title compound (641 mg) as a white solid. MS: [M+H]+=272.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:26])/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:26][CH2:17]/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: NC/C=C\c1ccccc1
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NC/C=C\c1ccccc1)C2

Procedure:
Starting from 1.02 g (0.005 mol) of 5-acetylamino-2-tetralone and 1.7 g (0.01 mol) of cis-cinnamyl-aminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.35 g (76.5% of theory) and with a melting point of 246° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:54]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:28][N:27]=[N:26][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[ClH:54]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nnn[nH]2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
In an 4-mL was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (16 mg, 0.043 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) and tetrabutylammonium fluoride trihydrate (20 mg, 0.057 mmol). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml) was added. The precipitate was collected by filtration and washed with water (5 ml) followed dichloromethane (5 ml). After dried, the title compound was obtained as a solid (13 mg, 71% yield, HCl salt, it is regioisomers). MW/HCl=448.41. 1H NMR (DMSO-D6, 360 MHz) δ 8.0 (s, brs, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 4.32 (s, 2H), 2.74 (q, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.11 (t, J=6.8 Hz, 2H). MS: ESI+, m/z 412 [M+H]+. LCMS: 98.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: NC1CCOCC1
Product: N#Cc1cnc(N)cc1NC1CCOCC1

Procedure:
From intermediate 21 and racemic tetrahydro-2H-pyran-4-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.36 min; ESI-MS 219.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:60](=[O:70])[CH2:61][C:62]3[CH:67]=[C:66]([CH3:68])[CH:65]=[CH:64][C:63]=3[CH3:69])[CH2:56][CH2:55]2)[S:52][CH:53]=1>C(#N)C>[CH3:69][C:63]1[CH:64]=[CH:65][C:66]([CH3:68])=[CH:67][C:62]=1[CH2:61][C:60]([N:57]1[CH2:56][CH2:55][CH:54]([C:51]2[S:52][CH:53]=[C:49]([NH:48][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:11])[N:50]=2)[CH2:59][CH2:58]1)=[O:70]
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(N)cs3)CC2)c1
Reactant: CC(C(=O)O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(NC(=O)C(C)c4ccccc4)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a solution of (rac.)-2-phenylpropionic acid (46 mg, 0.30 mmol) and diisopropylethylamine (0.15 mL, 0.9 mmol) in acetonitrile (2 mL) is added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (322 mg, 0.73 mmol) at RT. After stirring 30 min at RT, 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(2,5-dimethyl-phenyl)-ethanone (100 mg, 0.30 mmol) is added to the reaction mixture. After stirring overnight at RT, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (ethylacetate/cyclohexane 1:1) to give N-(2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-2-phenyl-propionamide (Compound No. I.g.141, 19 mg, 13.4%). 1H-NMR (400 MHz, CDCl3): δ=1.46-1.39 (m, 1H), 1.52 (d, 3H), 1.68-1.56 (m, 1H), 1.89-1.83 (m, 1H), 2.01-1.97 (m, 1H), 2.15 (s, 3H), 2.19 (s, 3H), 2.73-2.67 (m, 1H), 3.18-2.92 (m, 2H), 3.59 (s, 2H), 3.68-3.63 (q, 1H), 3.78-3.71 (m, 1H), 4.65-4.62 (m, 1H), 6.91-6.82 (m, 2H), 7.02-6.98 (m, 1H), 7.31-7.15 (m, 5H), 7.42 (s, 1H), 8.05 (br, 1H). MS: m/z=462 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(#N)C.O>[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:15]
Reactant: CCOC(=O)CCl
Reactant: Cc1ccccc1CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COC(=O)Cc1ccccc1C
Temperature: 25 °C

Procedure:
Potassium carbonate (25 g) was added to a stirred solution of o-tolylacetic acid (7.5 g) in acetonitrile (125 ml). The mixture was stirred for ten minutes at room temperature. Ethyl chloroacetate (6.13 g) was added and the mixture heated at reflux overnight. It was then poured into water, acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated, and purified by column chromatography to give ethoxycarbonylmethyl o-tolylacetate. Potassium carbonate 15 g) was added to a stirred solution of this product (10 g) in dimethylformamide (100 ml). The mixture was stirred at room temperature for 72 hours and then heated at reflux overnight. The mixture was cooled to 0° C. and potassium carbonate (5 g) added, followed by methyl iodide (2.65 ml). The mixture was stirred at room temperature for 24 hours. The mixture was poured into water, extracted with ether and the extract washed with brine, dried and evaporated to give 3-(2-methylphenyl)-4-methoxyfuran-2(5 H)-one, as a gum. This was then treated with N-bromosuccinimide followed by reaction with 2-mecaptobenzothiazole, in a similar manner to that described in Example 1, to give 3-[2-[[(2-benzothiazolyl)thio]methyl]phenyl]-4-methoxyfuran-2(5H)-one m.p. 81°-82°. (Compound 2)
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:10])[CH3:9]
Reactant: CCC(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A mixture of 5.00 g (48.0 mmols) of 2-hydroxybutyric acid, 4.98 ml (52.8 mmols) of acetic anhydride and 60 ml of pyridine was stirred at 0° C. for 10 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform) to give 7.01 g (yield, 100%) of 2-acetoxybutyric acid.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:25])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:11][C:12](=[O:25])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline n-decyl amide (12) (120 mg; 0.339 mmol) is dissolved in methylene chloride (4 mL) at ambient temperature. Trifluoroacetic acid (2 mL) is added and the solution is stirred for 2.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (20 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 5 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (80 mg) as an oil. ISMS: MH+ 254.8
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[CH2:16][Cl:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
4-bromoaniline (1.72 g, 10 mmol) was dissolved in 50 mL dichloromethane. Pyridine (cat.) was added and then 2-chloroacetyl chloride (800 uL, 10 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hr. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give the intermediate 7a (1.03 g, 4 mmol, 42% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.24 (broad s, 1H), 7.54-7.44 (m, 4H), 4.21 (s, 2H).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:10]([O:12][C:13](=[O:28])[C:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: c1cc2c(s1)CCNC2
Reactant: CCOC(=O)C(C)(C)CCC(Br)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (0.65 g, 4.61 mmol) and 5-bromo-5-(2-chlorophenyl)-2,2-dimethylpentanoic acid ethyl ester (1.42 g, 4.08 mmol) were dissolved in THF (5 mL) and triethylamine (3 mL) with a few crystals of DMAP. The solution was heated overnight to 85° C. using an oil bath. After 20 hours, the solution was cooled to room temperature and sodium bicarbonate solution (20 mL) was added. After mixing, the product was extracted with dichloromethane (2×25 mL). The combined dichloromethane fractions were dried over sodium sulfate, filtered, and concentrated. The remaining yellow oil was purified by MPLC on a Companion Chromatography station using silica gel (40 g), eluting with a gradient of 100% heptane to 10% ethyl acetate over 20 minutes followed by a second gradient to 100% ethyl acetate at 40 minutes. The second broad fraction was collected and concentrated to produce 5-(2-chlorophenyl)-5-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylpentanoic acid ethyl ester (Compound Ib, 1.11 g, 67.2% yield) as a light, yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.46 (dd, 1H, J=7.80, 1.5 Hz), 7.38 (dd, 1H, J=7.80, 1.5 Hz), 7.30-7.15 (m, 2H), 7.04 (d, 1H, J=5.1 Hz), 6.70 (d, 1H, J=5.1 Hz), 4.18 (dd, 1H, J=8.7, 4.5 Hz), 4.08 (q, 2H, J=7.2 Hz), 3.79 (d, 1H, J=14.4 Hz), 3.45 (d, 1H, J=14.4 Hz), 2.90-2.62 (m, 4H), 2.0-1.85 (m, 1H), 1.82-1.68 (m, 1H), 1.49 (dt, 1H, J=13.5, 4.2 Hz), 1.30 (dt, 1H, J=13.5, 4.5 Hz), 1.20 (t, 3H, J=7.2 Hz), 1.10 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.59, 138.99, 134.95, 134.25, 133.59, 129.64, 129.11, 128.07, 126.73, 125.43, 122.61, 63.81, 60.38, 50.63, 47.95, 42.22, 36.43, 28.22, 26.17, 25.52, 25.38, 14.47. MS (MMI-TOF): Calculated for C22H28NO2ClS (MH+): 406.1602; found 406.1576.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>CCOC(C)=O.[OH-].[Na+]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.4 %

Procedure:
To a solution of (S)-methyl 1-((4-nitrophenyl)sulfonyl)pyrrolidine-2-carboxylate (642 mg, 2.0 mmol) in EtOAc (10 mL) was added SnCl2.2H2O (2.02 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 2 d and diluted with EtOAc (50 mL) and 1 N NaOH (10 mL). The layers were separated and the aqueous phase re-extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo to yield the title compound as a white solid (531 mg, 93%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([NH2:11])[N:5]=1.FC(F)(F)S(O[CH2:18][CH3:19])(=O)=O.CO>CN(C=O)C>[CH2:18]([O:10][C:8]1[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([NH2:11])[CH:7]=1)[CH3:19]
Reactant: Nc1cc(O)nc(N)n1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1cc(N)nc(N)n1
Reaction time: 0.5 h

Procedure:
174 mg of sodium hydride (60% in mineral oil, 4.36 mmol) are added in portions under an argon atmosphere to a vigorously stirred solution of 500 mg (3.96 mmol) of 2,6-diaminopyrimidin-4-ol in 10 ml of DMF. After 30 min, 700 μl (5.15 mmol) of ethyl trifluoromethanesulfonate are added dropwise, and the solution is stirred for a further 20 min. Methanol (1 ml) is then added to the reaction mixture, which is directly purified by preparative HPLC. Combining the product fractions and removing the solvent result in 370 mg (64% of theory) of the title compound as a white solid.