Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[CH3:35]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][C:27]=1[CH3:35]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1C

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-3-methyl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[C:22]([N:31]3[CH2:36][C@H:35]([CH3:37])[CH2:34][C@H:33]([NH:38]C(=O)OC(C)(C)C)[CH2:32]3)=[C:23]3[CH2:29][CH2:28][CH:27]([OH:30])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:46].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C@H:33]1[CH2:34][C@@H:35]([CH3:37])[CH2:36][N:31]([C:22]2[C:21]([NH:20][C:18]([C:16]3[CH:15]=[CH:14][C:13]([F:46])=[C:12]([C:3]4[C:2]([F:1])=[CH:7][C:6]([CH2:8][O:9][CH3:10])=[CH:5][C:4]=4[F:11])[N:17]=3)=[O:19])=[CH:26][N:25]=[C:24]3[CH:27]([OH:30])[CH2:28][CH2:29][C:23]=23)[CH2:32]1
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](N)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The alcohol intermediated was treated with TFA (6 mL) and DCM (6 mL). The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resulting residue was purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two diastereoisomers of the title compound as white powders.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH:33]=[CH2:34])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:50][C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[C@H:59]([NH2:62])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])=[O:52].Cl>O.C(N(CC)CC)C.C(Cl)Cl>[C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[CH:59]([NH:62][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH:33]=[CH2:34])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])(=[O:52])[CH3:50]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 168.7 %

Procedure:
A mixture of 470 mg of the product of Step C, 5 ml of methylene chloride and 130 ml of dicyclohexylcarbodiimide was rinsed with a little methylene chloride and the mixture was stirred for an hour at room temperature. The mixture was vacuum filtered to remove the dicyclohexylurea formed and the filtrate was cooled. A solution of 136 mg of 7-amino-cephalosporanic acid, 2.4 ml of methylene chloride and 0.14 ml of triethylamine was added to the filtrate under an inert atmosphere and the mixture sat for 11/2 hours at room temperature. 2 ml of 1 N hydrochloric acid and water were added thereto and the mixture was stirred and decanted. The organic phase was washed with water, dried and evaporated to dryness to obtain 610 mg of raw 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-propenyl) oxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a syn configuration.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([NH:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[O:38])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)/[S:34][C:33]1=[O:38]
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: NCCN1C(=O)S/C(=C\c2ccc(O)cc2)C1=O

Procedure:
The title compound 30f was prepared from 4-hydroxybenzaldehyde (76 mg, 0.62 mmol), compound 29 (250 mg, 0.62 mmol) and piperidine (20.0 μL, 0.19 mmol) in a manner similar to that described for 30a in 43.0% (102 mg) yield as a yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:11][CH2:10][CH2:9][O:8][C:7]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>C(OCC)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: CC1=C(C(=O)O)OCCO1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC1=C(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)OCCO1

Procedure:
A mixture of thionyl chloride (1.3 g, 0.011 mole) and 5,6-dihydro-3-methyl-1,4-dioxin-2-carboxylic acid (0.57 g, 0.004 mole) was refluxed on a steam bath for 3 hours and the excess thionyl chloride was evaporated at atmospheric pressure. The resulting liquid was added dropwise to a stirred solution of 1-methylethyl 5-amino-2-chlorobenzoate (1.6 g, 0.008 mole) in diethyl ether (30 ml), cooled in an ice-water bath. The mixture was worked up by diluting with diethyl ether (120 ml), washing with dilute hydrochloric acid (50 ml), and then with water (50 ml). The diethyl ether solution was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure, leaving a solid residue. The crude product was washed with isopropyl alcohol (30 ml), leaving a brown solid, m.p. 103°-105° C. (1.2 g, 95.8% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.[CH:14](O)=[O:15]>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][O:12][CH:14]=[O:15])[CH2:3]1
Reactant: O=CO
Reactant: CC1(C)CC(CO)c2ccccc21
Product: CC1(C)CC(COC=O)c2ccccc21
Yield: 82 %

Procedure:
17.6 g (0.1 mol) of 1,1-dimethyl-3-hydroxymethylindane (IX) and 46.0 g (1.0 mol) of formic acid were reacted at room temperature for 16 hours while stirring. After the reaction, surplus formic acid was removed under reduced pressure. The residue was extracted with ether, washed with aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer and the residue was distilled under reduced pressure to produce 16.8 g (0.82 mol) of (1,1-dimethylindane-3-yl)methylformate at a yield of 82%. The product was a colorless, transparent liquid having a woody, green odor similar to green tea with a scent of rush.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Br[CH2:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:27].CCOC(C)=O>C1COCC1>[F:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)c(CN2CCOCC2)c1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A −20° C. mixture of DIEA (552 mg, 4.27 mmol) and morpholine (242 mg, 2.78 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 mL) and stirred overnight as the cooling bath expired. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.48 (t, J=9.1 Hz, 1H), 3.61 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.40 (t, J=4.4 Hz, 4H); MS (ESI) m/z: 241.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:32][C:33]1[CH:34]=[N+:35]([O-:58])[CH:36]=[C:37]([Cl:57])[C:38]=1[CH2:39][C@@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([O:22][C@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:50])[F:51])=[C:44]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:43]=1)[CH2:39][C:38]1[C:37]([Cl:57])=[CH:36][N+:35]([O-:58])=[CH:34][C:33]=1[Cl:32])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol) in dry DCM (16 ml), EDC (0.157 g, 0.818 mmol) and DMAP (0.050 g, 0.409 mmol) were added followed by (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.172 g, 0.409 mmol), and the resulting solution was stirred overnight at RT. Additional EDC (0.080 g, 0.42 mmol) and DMAP (0.025 g, 0.20 mmol) were added, and the reaction was stirred at the same temperature for 24 hours. The mixture was partitioned between DCM and HCl 1N; the organic phase was washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed and the crude was purified by preparative HPLC affording (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.082 g, 0.100 mmol, 24.4% yield, MS/ESI+ 821.1 [MH]+).
Reaction SMILES: ClC1C=CC(CC(=O)CC2C=CC=C(C(F)(F)F)C=2)=CC=1.C(OCC)=O.Cl.CN.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:42](=[O:43])[C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=3)=[CH:40][N:39]([CH3:54])[CH:38]=2)=[CH:33][CH:32]=1.N1C=CC=CC1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[C:42](=[O:43])[CH:41]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:51])[F:52])[CH:45]=3)[CH2:40][N:39]([CH3:54])[CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cn1cc(-c2ccc(Cl)cc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CN
Agent: Cl
Agent: O=C(Cc1ccc(Cl)cc1)Cc1cccc(C(F)(F)F)c1
Solvent: CCOC=O
Product: CN1CC(c2ccc(Cl)cc2)C(=O)C(c2cccc(C(F)(F)F)c2)C1

Procedure:
A 15 g. portion of 1-(4-chlorophenyl)-3-(3-trifluoromethylphenyl)-2-propanone was reacted with ethyl formate and methylamine hydrochloride to prepare 10 g. of 3-(4-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone. The intermediate pyridinone was reduced with lithium aluminum hydride. Column chromatographic separation of the reaction mixture on a silica gel column as described in the examples above produced about 0.5 g. of the compound of Example 18, m.p. 122.5°, about 1.1 g. of the compound of Example 19, m.p. 113.5°, and about 1.3 g. of the compound of Example 20, m.p. 115.5°.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9](OCC)=O.[CH3:14][NH2:15]>CO>[CH3:14][NH:15][CH2:9][C:2]1[S:1][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1cc2ccsc2s1
Solvent: CO
Product: CNCc1cc2ccsc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A suspension of ethyl thieno[2,3-b]thiophene-2-carboxylate (3.84 g, 18.1 mmole) in 40% aqueous CH3NH2 (100 mL) and MeOH (10 mL) was stirred at RT for 18 hr. During that time the suspension became a solution. The mixture was concentrated to approximately ⅓ volume at which time the product precipitated. The solid was collected by filtration, washed with H2O, and dried in vacuo to give the title compound (3.01 g, 85%): 1H NMR (400 MHz, d6-DMSO) δ 8.60 (bs,1H), 7.92 (s,1H), 7.67 (d, J=5.2 Hz, 1H), 7.38 (d, J=5.2 Hz,1H), 2.78 (d, J=4.6 Hz. 3H).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)=[N:25][OH:26].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)(=O)C.O>[CH2:1]([N:8]([CH2:23][C:24]([C:27]1[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=1)=[N:25][OH:26])[C@@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(CBr)c1cc(F)cc(F)c1
Reactant: COC(=O)[C@H](CC1CCCCCC1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1

Procedure:
820 mg (2.83 mmol) methyl (S)-2-benzylamino-3-cycloheptyl-propionate were stirred overnight at RT together with 0.71 g (2.83 mmol) 2-bromo-1-(3,5-difluoro-phenyl)-ethanone-oxime, 0.51 g (3.68 mmol) potassium carbonate and 10 ml THF. After the addition of water and ethyl acetate the organic phases were combined, washed with water, dried and evaporated to dryness by rotary evaporation. The residue was purified by RP-HPLC. The product-containing fractions were combined, the organic solvent was removed and the aqueous residue was made alkaline with saturated, aqueous sodium hydrogen carbonate solution. It was extracted with ethyl acetate, the organic phase was dried and concentrated by rotary evaporation.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].[C-:16]#[N:17].[Na+]>CCO.O>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][C:16]#[N:17])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: [C-]#N
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 258 (0.8 g, 2.8 mmol) and EtOH:water (4:1) was heated to 50° C. was added NaCN (0.20 g, 4.2 mmol) and the reaction stirred at 50° C. overnight. The reaction was then cooled and concentrated to dryness then partitioned between H2O and EtOAc. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 3:1) to afford 0.5 g (77%) of (S)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile (282).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[C:8]2S)=[CH:4][CH:3]=1.OO.[OH-].[Na+]>CO.O[W](O)(=O)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cnc(S)n1Cc1ccc(Br)cc1
Agent: O=[W](=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: OCc1cncn1Cc1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
1-(4-Bromobenzyl)-2-mercapto-5-hydroxymethylimidazole(1.5 g, 5 mmol) and tungstic acid(12.5 mg, 1 mol %) were suspended in 7 ml of methanol. The suspension was warmed to 40° C. and then, 30% hydrogen peroxide was slowly added dropwise. After about 2 hours, the mixture was cooled and neutralized with 1 N sodium hydroxide solution, and the precipitate was filtered. The obtained solid was washed twice with 5 ml of distilled water and 5 ml of isopropyl ether, respectively, to give 1.1 g(Yield 82%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@:4]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[O:23][N:22]=2)([CH3:20])[CH2:3]1.[Na].[CH3:34]I>CS(C)=O>[CH3:34][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@:6]([O:18][CH3:19])([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@:4]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[O:23][N:22]=2)([CH3:20])[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: CI
Reactant: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Agent: [Na]
Solvent: CS(C)=O
Product: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2 g of 6-methyl-8β-methyl-[5-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-10α-methoxy-ergoline in ml 30 of dimethylsulphoxide was added at room temperature, 0.5 g of finely ground sodium hydroxyde. After stirring for 30 mins., a solution of 0.9 g of methyl iodide in m 10 of dimethylsulphoxide was added and the stirring was continued for 1 hour.
Reaction SMILES: [C:1]1([C:7]([OH:23])([CH2:9][CH2:10][NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:8][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:23][C:32](=[O:34])[N:11]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)(CCNc1nc(-c2ccccc2)cs1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(c2ccccc2)CCN(c2nc(-c3ccccc3)cs2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
To a solution of 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (50 mg, 0.15 mmol) and Et3N (80 mg, 0.75 mmol) in CH2CH2 (5 mL) was added triphosgene (15 mg, 0.05 mmol) at 0° C. Then, the mixture was stirred at rt overnight. The reaction solution was concentrated to give an oil, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 6-methyl-6-phenyl-3-(4-phenylthiazol-2-yl)-1,3-oxazinan-2-one (20 mg, 37%). LC-MS Method 3, tR=1.446 min, m/z=351. 1H NMR (CDCl3, 400 Hz): 1.80 (s, 3H), 2.45 (m, 1H), 2.65 b (m, 1H), 3.70 (m, 1H), 4.42 (m, 1H), 7.18 (s, 1H), 7.20-7.40 (m, 8H), 7.80 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CS(O[CH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C(OCC)(=O)C>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:29][C@H:30]4[CH2:34][CH2:33][N:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:31]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC[C@H]4CCN(c5ccccn5)C4)c(C(F)(F)F)c3)cc21

Procedure:
6-(4-Hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.313 mmol, 0.1 g), (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate (0.376 mmol, 0.096 g), cesium carbonate (0.470 mmol, 0.153 g) and tetrabutylammonium idodide (0.157 mmol, 0.058 g) were stirred in DMF (1 ml) at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. The resulting residue was triturated with ether and filtered. The solid was sonicated in methanol, filtered and dried to afford (S)-1-methyl-6-(4-((1-(pyridin-2-yl)pyrrolidin-3-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (0.032 g)
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl.CO>CO.C(Cl)Cl>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=2)[CH2:11][CH2:10]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ccccc2c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@H](O)CC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the title compound from step 1 (180.0 mg, 0.33 mmol) in dry MeOH (5 mL) and DCM (3 mL) was added dropwise HCl/MeOH (0.3 mL, 1.2 mmol, 4M) at 0° C. and then stirred at r.t. for 20 min. TLC showed the starting material was consumed completely. The mixture was concentrated and the residue was purified by prep-HPLC to afford the title compound (130.0 mg, 97.8%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 7.98 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.55 (t, J=6.8 Hz, 1H), 7.51 (t, J=6.8 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.42-4.35 (m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.10 (s, 3H), 2.01-1.89 (m, 2H), 1.71-1.65 (m, 2H), 1.36-1.34 (m, 4H). LCMS (M+H)+=428.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[NH:18][C:19](=S)[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:18]=[C:19]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(Cl)cc3Cl)n(CCCCO)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A suspension of methyl 4-chloro-3-{[(3,5-dichloropyridin-2-yl)carbamothioyl]amino}-2-[(4-hydroxybutyl)amino]benzoate (2.76 g, 5.78 mmol), triethylamine (886 μL, 6.36 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.22 g, 6.36 mmol) in tetrahydrofuran (25 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (2.45 g, 5.52 mmol, 96%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[N:11]O)[NH:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.[OH-].[NH4+]>>[F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][N:6]2[N:11]=1
Reactant: ON=C(Nc1cnccn1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: FC(F)(F)c1nc2cnccn2n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 2,2,2-trifluoro-N′-hydroxy-N-pyrazin-2-ylethanimidamide (10.5 g, 50.97 mmol, from Step B) and polyphosphoric acid (80 mL) was heated to 150° C. with stirring for 18 h. The solution was added to ice and neutralized by addition of ammonium hydroxide. The dark aqueous solution was extracted three times with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography (eluting with 50% followed by 100% ethyl acetate/hexane) afforded the title compound as a yellow solid.