Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH2:14])=[N:9][C:8]=1[NH2:15])[CH3:2].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH:14][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[N:15]([C:23](=[O:25])[CH3:24])[C:12](=[O:13])[CH3:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCc1c(N)nc(N)[nH]c1=O)OCC
Solvent: c1ccncc1
Product: CCOC(CCc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 7.20 g (28.1 mmol) of 3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde diethyl acetal, 30 ml of dry pyridine and 30 ml of freshly distilled acetic anhydride was heated on an oil bath at 90° for 6 hours and then stirred at ambient temperature overnight. Solution occurred within 15 minutes as a mixture of diacetyl and triacetyl pyrimidinone formed; extended reaction was required to obtain only the title compound. The solution was spin evaporated in vacuo to give an oil. Ethyl acetate was added and spin evaporated several times until a solid was obtained. The solid was dispersed in cyclohexane and collected; yield, 8.88 g (82%), mp 126°-137° (one spot on TLC). Recrystallization of a portion from cyclohexane-ethylacetate gave the analytical sample, mp 138°-139°; TLC (C6H6 :EtOH/5:1); NMR (DMSO-d6) δ1.08 (t, 6H, 2CH2CH3), 1.63 (m, 2H, CH2CH2CH), 2.13 (s, 3H, Ac), 2.27 (s, 6H, 2Ac), 2.2 (2H, CH2CH2CH, superimposed on the acetyl singlets), 3.2-3.7 (m, 4H, 2×OCH2), 4.42 (t, 1H, CH), 11.87 (br s, 2H, AcNH and HNC(O)).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.N1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.[OH-:26].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[Cl:2][C:3]1[C:4]([C:5]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:26])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: [OH-]
Reactant: COc1ccc(N)cc1
Reactant: ClCc1cccnc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccnc2Cl)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
2-Chloronicotinyl chloride hydrochloride (2.94 g, 16.5 mmol) was added in portions to a solution of pyridine (4.0 mL) and 4-anisidine (2.0 g, 16.2 mmol) in chloroform. After 0.5 h, the mixture was poured into EtOAc and 1 N NaOH. The organic layer was washed with 1 N NaOH (1×), water (1×), dried over potassium carbonate, and concentrated. The residue was purified by recrystallization (EtOAc:hexanes) yielding 2.56 g (60%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[S:32])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2NC1=O
Solvent: c1ccncc1
Product: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2NC1=S

Procedure:
730.6 mg (1.696 mmol) of 2-methyl-3-oxo-6-[2-(3-chlorobenzyl-tert-butyloxycarbonylamino)-ethyl]-3,4-dihydro-2H-1,4-benzoxazine is mixed in 8 ml of pyridine with 201.1 mg (0.607 mmol) of phosphorus pentasulfide, and then it is refluxed for four hours. The solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). The yield is 439.3 mg (58%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:21]=[C:20]([O:22][C:23]2[CH:24]=[N:25][C:26]([CH:30]3[CH2:32][CH2:31]3)=[C:27]([Cl:29])[CH:28]=2)[C:19]([Cl:33])=[CH:18][C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12]>ClCCl>[Cl:8][C:9]1[CH:21]=[C:20]([O:22][C:23]2[CH:24]=[N:25][C:26]([CH:30]3[CH2:32][CH2:31]3)=[C:27]([Cl:29])[CH:28]=2)[C:19]([Cl:33])=[CH:18][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
Trifluoroacetic acid (42 μL, 0.56 mmol) was added to a solution of tert-butyl 2,5-dichloro-4-(5-chloro-6-cyclopropylpyridin-3-yloxy)benzoate (Preparation 219, 116 mg, 0.28 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 4 hours then concentrated in vacuo. The residue was dissolved in methanol (10 mL) then concentrated in vacuo to afford the title compound as colourless solid (100 mg, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:45])(=[O:44])[NH:39]C(C)(C)C)=[CH:28][C:27]=2[F:46])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:44])(=[O:45])[NH2:39])=[CH:28][C:27]=2[F:46])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(C)(C)C)cc3F)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 32 mg (0.048 mmol) of 5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step F) in 0.5 mL of trifluoroacetic acid (TFA) containing 2 drops of anisole was stirred overnight at room temperature. The excess TFA was removed by evaporation under a gentle stream of N2. The residue was reconcentrated from toluene twice in vacuo and flash chromatographed over 15 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) to give 20 mg (69%) of the title compound as a white solid, mp 108°-110° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 614 (M+1)+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:13]=[CH:12][C:11]=2[OH:21])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:22]=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(O)CCC>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:13]=[C:12]([CH2:22][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:11]=2[OH:21])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCNCC
Reactant: C=O
Reactant: OCCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: CCCCO
Product: CCN(CC)Cc1cc(CCCCO)cc(-n2nc3ccccc3n2)c1O
Temperature: 105 °C
Yield: 97 %

Procedure:
In 25 ml of n-butanol were dissolved 28.3 g (0.1 mols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(4-hydroxybutyl)phenol synthesized in Example 16, 5.2 g of 80% paraformaldehyde and 11.0 g (0.15 mols) of diethylamine. The solution was refluxed with heating at 105° C. for 24 hours. After completion of the reaction, the solvent and remaining raw materials were collected under reduced pressure, giving 37.4 g of objective 2-(2H-benzotriazole-2-yl)-4-(4-hydroxybutyl)-6-(N,N-diethylaminomethyl)phenol as a brown oil (yield 97.0%, purity 95.6%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]=[CH:6]2
Reactant: OC1CCc2c(Br)cccc21
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cccc2c1CC=C2
Temperature: 20 °C
Yield: 89.6 %

Procedure:
30 g of 4-bromo-1-indanol is dissolved in 720 ml of toluene, 27 g of paratoluene sulphonic acid is added, then 0.93 g of 4-tertbutylcatechol is added. The mixture is taken to reflux for one hour. After cooling to 20° C., the organic phase is washed with 25 ml of N sodium hydroxide, dried and concentrated to dryness, and the residue is chromatographed on silica, eluting with a hexane-difluoro dichloro ethane mixture (95-5), and 24.6 g of expected product is isolated.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:24])([F:23])[F:22])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:50](=[O:65])[C:51]1[CH:56]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:54]=[C:53]([S:61]([CH3:64])(=[O:63])=[O:62])[CH:52]=1>C(Cl)Cl>[CH3:64][S:61]([C:53]1[CH:52]=[C:51]([CH:56]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:54]=1)[C:50]([N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]([F:23])([F:24])[F:22])=[O:65])(=[O:63])=[O:62]
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC(F)(F)F
Yield: 13 %

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methanesulfonyl-ethyl)-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-amine, DIPEA and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) in CH2Cl2 after a reaction time of 12 hours at 25° C. The crude thus obtained was purified by preparative HPLC (ammonium acetate/acetonitrile) to furnish the title compound as an off-white solid (15 mg, 13%). MS (ESI): m/z=611.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][C@H:23]([CH2:26][CH3:27])[CH2:24]O)(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (3.00 g, 13.3 mmol) was reacted with N-Boc-(R)-(+)-2-amino-1-butanol (2.76 g, 14.6 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 1.48 g (41%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ. 0.87-0.94 (m, 3H), 1.11-1.40 (m, 2H), 2.97-3.06 (m, 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.84 (m, 1H), 6.96 (d, 1H), 7.86 (d, 1H), 7.94 (dd, 1H), 7.97 (dd, 1H), 8.09-8.11 (m, 1H). MS [M+1]: m/z [274.8+1].
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8](=O)[C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1CCCC(=O)C(=O)C1)(=O)C.Br.Br.[NH2:27][CH2:28][C:29]([NH2:31])=[NH:30]>>[NH2:31][C:29]1[CH:28]=[N:27][C:8]2[CH2:9][CH2:10][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][C:7]=2[N:30]=1
Reactant: N=C(N)CN
Reactant: CC(=O)N1CCC(=O)C(=O)CC1
Agent: Br
Agent: CC(=O)N1CCCC(=O)C(=O)C1
Product: CC(=O)N1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 13 by reacting a mixture of 1-acetyl-hexahydroazepine-4,5-dione and 1-acetyl-hexahydroazepine-3,4-dione (prepared from 1-acetylhexhydroazepine-4-ones by selenium dioxide oxidation in dioxane/water) with 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5](=[O:8])[N:6]([CH2:20][CH3:21])[CH:7]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(Br)cc(C(F)(F)F)c1=O
Temperature: 25 °C
Yield: 67 %

Procedure:
In a round bottom flask equipped with a stir bar and purged with nitrogen was added 5-bromo-3-(trifluoromethyl)pyridin-2-ol (1.0 equiv.), potassium carbonate (2.0 equiv.) and DMF (0.2 M). The mixture was stirred at room temperature and iodoethane (1.2 equiv.) was added via syringe. The mixture was warmed to 35° C. for 4 hours at which time LCMS indicated full conversion. The reaction was worked up by partitioning between water and ethyl acetate, the aqueous phase was extracted 3 more times with ethyl acetate, the organics were combined, washed with brine, dried with sodium sulfate, filtered and concentrated to yield 5-bromo-1-ethyl-3-(trifluoromethyl)pyridin-2(1H)-one (67%). 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.50 (m, 3H) 4.04 (q, J=7.17 Hz, 2H) 7.63 (br. s., 1H) 7.78 (br. s., 1H). LCMS (m/z) (M+H)=269.1/271.1, Rt=0.72 min
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].[NH3:28]>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH2:28])[N:10]=1
Reactant: N
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(COCCCOn1cnc2c(N)nc(N)nc21)OCC
Yield: 32 %

Procedure:
A solution of 6-chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]-2-formamidopurine (1.2 g, 2.85 mmol) in ethanolic ammonia (25 ml) was heated at 110° C. in an autoclave for 7.5 h then left to cool for 12 h. The reaction was then evaporated in vacuo and the residue chromatographed on silica eluting with chloroform/methanol (10:1) to give 2,6-diamino-9-[3-(diethoxyphosphorylmethoxy)propoxy]purine as a pale yellow solid (0.34 g, 32%); νmax (KBr) 3313, 3149, 1586, 1481, 1240, 1054 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz,(CH3CH2O)2), 1.91(2H, m, CH2CH2CH2), 3.70(2H, t, J6 Hz, CH2OCH2P), 3.84(2H, d, J7.98 Hz,CH2P), 4.04(4H, m,(CH3CH2O)2), 4.31(2 H, t, J6.5 Hz, NOCH2), 5.93(2H, br.s, D2O exchangeable, NH2), 6.77(2H, br.s, D2O exchangeable, NH2), 7.94(1H, s, H-8); Found C, 41.25; H, 6.32; N, 22.65%; M+ 374.1477; C13H23N6O5P.0.2H2O requires: C, 41 31; H, 6.35; N, 22.24%; M+ 374.1468.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Compound 157 (3.52 g, 12.3 mmol) was dissolved in anhydrous THF (123 mL) and cooled to 0° C. Borane dimethylsulfide complex (10 M, 3.69 mL) was added dropwise, and the reaction then warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0° C., and quenched with MeOH (20 mL) added dropwise. The reaction was stirred for 18 hours, and the solvent rotovapped off. The crude material was chromatographed on silica eluting with 20% EtOAc/hexanes to give 158 (2.28 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) δ 3.65–3.59 (m, 1H), 3.43 (dd, J=11.1, 6.96 Hz, 1H), 2.31 (dd, J=14.9, 7.57 Hz, 1H), 2.21 (dd, J=15.1, 5.62 Hz, 1H), 2.06–2.02 (m, 1H), 1.43 (s, 9H), 1.40–1.25 (m, 4H), 1.07–1.13 (m, 1H), 1.03–0.96 (m, 1H), 0.86–0.84 (m, 6H); MS (APCI) m/z 216 (M+−56, 100%).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH:26]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[O:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([CH:23]2[CH2:22][NH:21][CH2:24]2)=[CH:26]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(c3coc4ccccc34)C2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cl
Product: c1ccc2c(C3CNC3)coc2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 133.5 %

Procedure:
1-Chloroethyl chloroformate (18 μL, 0.16 mmol) was added to a solution of 1-benzhydryl-3-(benzofuran-3-yl)azetidine (52 mg, 0.15 mmol) in dichloromethane (1.5 mL) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and for 4 hours at room temperature. An additional amount of 1-chloroethyl chloroformate (8 μL, 0.07 mmol) was added and stirring continued for 1 hour at room temperature. Ethanol (1.5 mL) was added and the reaction mixture was stirred for 3 days at room temperature. After concentration to dryness, the crude mixture was triturated in n-pentane (2×2 mL) to afford the title compound as a pink solid (42 mg, 130%) which was used without further purification.
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:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH: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:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc(Cl)c1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Chloro-benzoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][C:10]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C=C(C(C)C)C=CC=1O)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1
Agent: CC(C)c1ccc(O)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Product: CC(C)(C)c1cc(Cc2ccccc2O)cc(C(C)(C)C)c1O

Procedure:
2-(3,5-ditert.-butyl-4-hydroxybenzyl)-5-methylphenol and 2-(3,5-ditert.-butyl-4-hydroxybenzyl)-4-isopropylphenol;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].CN.O.O[N:35]1[C:39]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:35][CH3:39])=[O:27])=[C:13]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC-HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: [I:1]I.[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:3][C:4]1[C:11]([I:1])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1
Reactant: CSc1nc(O)ccc1C#N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CSc1nc(O)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
6 g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) of iodine are added successively to a solution of 2 g (12 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 200 ml of ethanol. The reaction medium is stirred at room temperature for 2 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and then taken up in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 3.18 g (90%) of 6-hydroxy-5-iodo-2-(methylthio)nicotinonitrile in the form of a yellow powder.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1.CO>CN(C)C=O.ClCCl>[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([O:14][CH3:1])=[O:13])=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a 0° C. suspension of Example 324a (5.47 g, 14.6 mmol) and dichloromethane (65 mL). 3 drops dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. After cooling to 0° C., methanol (12 mL, 296 mmol) was added dropwise. The solution was stirred for 15 minutes at 0° C. and for 2.5 hours at ambient temperature. The solution was diluted with dichloromethane and was washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (5.42 g, 96% yield).