Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[SH:33][CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][S:33][CH:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18]1(=[O:26])=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(S)C1
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(SCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 84 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. tert-Butyl 3-mercaptopyrrolidine-1-carboxylate (70 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (134 mg, 83.4%). The product is a mixture of cis and trans isomers. 1H NMR (CDCl3, 500 MHz): δ 1.47 (s, 9H), 1.73 (s, 10H), 2.05 (s, 1H), 2.46-2.51 (m, 2H), 2.88 (bs, 1H), 3.01-3.13 (m, 3H), 3.29 (s, 1H), 3.41-3.57 (m, 2H), 5.65 (bs, 1H), 7.43-7.46 (m, 3H), 7.49-7.53 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.83, 28.73, 31.29, 32.33, 32.86, 41.74, 42.41, 43.23, 44.86, 45.09, 52.27, 52.53, 61.86, 79.79, 108.04, 125.15, 129.04, 130.04, 131.65, 134.81, 154.41, 159.66; Mass Spectrum: M+H+ 509.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:17]2[CH2:20][CH:19]([C@H:21]([C:26]3[CH:31]=[C:30](F)[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:17]2[CH2:18][CH:19]([C@H:21]([C:26]3[CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:23])[CH3:24])[CH2:20]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(F)[C@@H](c1cc(F)cc(F)c1)C1CN([C@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(F)[C@@H](c1cc(F)cc(-n2ccnc2)c1)C1CN([C@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 90 mg (0.192 mmole) of 3-((R)-(4-chlorophenyl){3-[(1R)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 17 mg (0.25 mmole) of imidazole and 40 mg (0.288 mmole) of K2CO3 in 1.5 mL DMSO was stirred at 150° C. in a microwave (with cooling). After 4 h, the mixture was poured into 30 mL of ether and 5 mL of water. The layers were separated and the aqueous layer was washed with three 10 mL portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 25% acetone-hexane to afford the title compound; Mass Spectrum: m/e=517 (M+1, 35Cl); 519 (M+1, 37Cl).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:26](=[S:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=1[C:28]([F:29])([F:30])[F:31]
Reactant: FC(F)(F)c1cc(Cl)ccc1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2C(F)(F)F)c1NCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.8 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (12.5 g, 48.3 mmol) and 4-chloro-1-isothiocyanato-2-(trifluoromethyl)benzene (14.9 g, 62.8 mmol) in tetrahydrofuran (150 mL) was stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-({[4-chloro-2-(trifluoromethyl)phenyl]carbamothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate as a brown oil (22.0 g)
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[O:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[C:29]([O:31][CH3:32])=[O:30])[CH2:20]1.CN1CCNCC1C(OC)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH:21]3[CH2:22][O:19][CH2:20]3)[CH:24]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C1CNCCN1C1COC1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: COC(=O)C1CNCCN1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CCN1C1COC1
Temperature: 105 °C
Yield: 18.8 %

Procedure:
(+/−) Tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (1.52 g, 4.58 mmol), a 3:1 mixture of methyl 1-(oxetan-3-yl)piperazine-2-carboxylate (0.688 g, 3.44 mmol) and methyl 1-methylpiperazine-2-carboxylate (0.181 g, 1.144 mmol), Pd2(dba)3 (0.420 g, 0.458 mmol), BINAP (0.285 g, 0.458 mmol), Cs2CO3 (2.240 g, 6.88 mmol), and Toluene (40 mL) were combined in a round bottom flask. The flask was evacuated and backfilled with N2 3×, and the reaction was heated at 105° C. for 18 h. The reaction was cooled to room temperature and an additional 0.05 eq. each of catalyst and ligand were added. The reaction vial was resealed, evacuated and backfilled with N2 3×, then heated at 105° C. for 2 h. The reaction was cooled to room temperature and diluted with EtOAc. The solution was filtered through celite and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography 0-5% MeOH/DCM, and then repurified with 0-20% Acetone/DCM. 292 mg of pure methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate was obtained, along with 592 mg of a 3:1.7 mixture of methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate and methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methylpiperazine-2-carboxylate. Estimated yields based on 1H NMR: methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate (683 mg) and methyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-methylpiperazine-2-carboxylate (201 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1ccc(Cl)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichloro-4-fluorobenzene and isolated as white solid. MS (m/e): 459.2 (MH+).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C([O-])(O)=O.[Na+]>O1CCCC1>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CO
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
30 ul of boron trifluoride etherate were added to a suspension of 216 mg (1.15 mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 400 mg (2.3 mmols) of freshly prepared tert.-butyl 4-hydroxyacetoacetate in 4 ml of anhydrous tetrahydrofuran at room temperature. After a short time a clear, light yellow solution formed, which was stirred for 0.5 hour at room temperature. It was then poured into dilute NaHCO3 solution. The mixture was extracted with methylene chloride, washed with water and dried over magnesium sulphate. After the solvent had been evaporated off in vacuo and the residue had been chromatographed on 60 g of silica gel (toluene:ethyl acetate 1:3), 128 mg (31%) of tert.-butyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]acetoacetate were obtained as colorless crystals, melting point: 142° C., RF : 0.36 (toluene:ethyl acetate 1:4), [α]D20 =32.24° (0.955 percent in CHCl3).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:43]([C:41]2[CH:40]=[N:39][N:38]([S:35]([C:33]3[CH:32]=[CH:31][C:22]4[N:23]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:19]([C:15]([CH3:14])([CH3:18])[CH2:16][CH3:17])=[N:20][C:21]=4[CH:34]=3)(=[O:37])=[O:36])[CH:42]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Yield: 42.3 %

Procedure:
Following the same procedure in Example 24, Step A, using cyclopropylamine (21 mg, 25 uL, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 38 mg (42%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.54-0.61 (m, 2 H), 0.74-0.82 (m, 5 H), 1.42-1.58 (m, 4 H), 1.60 (s, 6 H), 1.96 (q, J=7.55 Hz, 2 H), 2.22-2.36 (m, 1 H), 2.73-2.80 (m, 1 H), 3.26-3.36 (m, 2 H), 3.86-3.95 (m, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.34 (d, J=1.76 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=500.0; Anal. Calcd for C25H33N5O4S+0.6 TFA+1.0H2O (586.07): C, 53.70; H, 6.12; N, 11.95. Found: C, 53.65; H, 5.98; N, 12.02.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5]([NH:7][NH2:8])=O)[CH3:2].[C:10](=[S:12])=[S:11].[OH-].[K+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:11][C:10]([SH:12])=[N:8][N:7]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)C(=O)NN
Reactant: S=C=S
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1nnc(S)s1
Temperature: 55 °C

Procedure:
Scheme 1 shows a synthetic method that may be used to prepare compounds of formula I-III. First, hydrazino-oxo-acetic acid ethyl ester 1 (prepared by the method of Berdinskii, I. S.; Maslivets, A. N. Hydrazides of disubstituted glycolic acids. Zh. Org. Khim. (1982), 18(9), 1839-43) is treated with carbon disulfide (excess) and KOH (1.0 equiv.) in ethanol at 0° C. to give 2. Treatment of 2 with cold (excess) sulfuric acid for 20 minutes followed by heating to 55° C. for 1 hour gives 5-mercapto-[1,3,4]-thiadiazole-2-carboxylic acid ethyl ester which is then treated with ethyl iodide and potassium carbonate in ethanol/water at room temperature to give 3. Heating compound 4 in the presence of benzylamine gives the amide, which is oxidized to the sulfone 5 with m-chloroperbenzoic acid (2.5 equiv) in chloroform or methylene chloride at room temperature. Treatment of 5 with 3-oxo-pentanoic acid methyl ester and excess sodium hydride in refluxing tert-butanol for 48 hours gives 6 after flash silica purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.26 mol) and iodomethane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70° C. for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1e (44.59 g, yield 90.0%) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([CH:10]2[CH:9]1[CH3:26])=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.S(=O)(=O)(O)O.[Br:33]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([CH:10]2[CH:9]1[CH3:26])=[CH:17][C:16]([Br:33])=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1C2c3cccc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC1C2c3cc(Br)cc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (364 mg, 0.98 mmol) was added concentrated aqueous hydrogen chloride (5 mL). The resulting mixture was stirred for five minutes and then concentrated. The resulting residue was treated with concentrated aqueous sulfuric acid (2.0 mL) and N-bromosuccinimide (193 mg, 1.1 mmol). The resulting brown solution was degassed (vacuum then argon), covered with aluminum foil and stirred in the dark for 24 h. The reaction was then diluted with ice water and basified with saturated aqueous sodium bicarbonate. The resulting mixture was diluted with ethyl acetate (15 mL) and treated with di-tert-butyl dicarbonate (excess). After 1 hr, the reaction washed with ethyl acetate (3×50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, 0-30% ethyl acetate in hexanes) to afford N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-bromo-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (261 mg, 59%) as a white foam-like solid. MS (ESI) 449, 451 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])([O-])=O>C(O)C.O.NN.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)N2CCOCC2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
The compound ([13]-(132)-158) (8.63 g) prepared in Example 83 was dissolved in ethanol (400 ml), and the solution was heated to 50° C. To the suspention, a solution of 10% Pd/C (2.25 g) in ethanol and hydrazine monohydrate (4.4 ml) were added to the solution. The mixture was stirred for 30 minutes. After the reaction was completed, the catalyst was removed by filtration through celite. The solution was concentrated, and the residue was purified by silica gel column chromatography (Kieselgel 60=120 g, ethyl acetate) to obtain the above-captioned compound ([13]-(133)-158) (7.57 g) as a white solid,
Reaction SMILES: [NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19]([CH3:21])=O)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1.SC[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19][CH2:21][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(C2(N)CC=C3C=CC=C3O2)ncc1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cnc(C2(N)CC=C3C=CC=C3O2)nc1SCCc1ccccn1

Procedure:
From 2-amino-4-benzofuran-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%:374 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:29]>C(O)C.O>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+:29]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(F)c1
Reaction time: 4 h

Procedure:
A mixture of 3.62 g. of 2-fluoro-4-(hexadecylamino)-benzoic acid and 25 ml of ethanol-water (9:1) containing 0.400 g of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml of ethanol-water (9:1) and dried, in vacuo, over P2O5 for 24 hours to yield sodium 2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[CH:3]=1.Cl.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:14]=[O:15]
Reactant: CCCn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 34.3 g (0.20 mol) of 6-amino-1-propyl-2,4-(1H,3H)-pyrimidinedione (II), dissolved in 900 ml hot water, was added 45 ml of 5 N HCl and 15 g of NaNO2 (0.22 mol) which was dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 33.3 g (83%) (III) NMR.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([NH:22]C(=O)C)=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]>Cl>[CH3:5][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:8]=2[N:7]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1nc2cc(NC(C)=O)ccc2n1CC1CCOCC1
Agent: Cl
Product: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step G, using N-[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]acetamide (2.08 g, 6.06 mmol) in 37% HCl (20 mL). Yield: 1.81 g (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.79 (t, J=7.52 Hz, 3 H), 1.42-1.51 (m, 4 H), 1.52 (s, 6 H), 1.84 (q, J=7.42 Hz, 2 H), 2.15-2.37 (m, 1 H), 3.25-3.38 (m, 2 H), 3.59 (s, 2 H), 3.92-4.03 (m, 2 H), 4.12 (d, J=7.42 Hz, 2 H), 6.65 (dd, J=8.50, 2.25 Hz, 1 H), 7.06 (d, J=2.15 Hz, 1 H), 7.10 (d, J=8.01 Hz, 1 H); MS (ESI) (M+H)+=301.98.
Reaction SMILES: [Li+].[Cl-].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C(N(CC)C(C)C)(C)C.[CH3:26][C:27]([S@:30]([NH:32][C@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([C:37]([F:41])([F:40])[CH:38]=O)[CH:34]([F:36])[F:35])=[O:31])([CH3:29])[CH3:28]>C(#N)C>[C:27]([S@:30]([NH:32][C@@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH:34]([F:35])[F:36])[C:37]([F:40])([F:41])[CH:38]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:31])([CH3:26])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[S@@](=O)N[C@@](c1ccccc1F)(C(F)F)C(F)(F)C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C=CC(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred suspension of LiCl (405 mg, 9.56 mmol) in acetonitrile (30 mL) under N2 were added ethyl 2-diethoxyphosphorylacetate (2.14 g, 9.56 mmol) and DIPEA (N,N-diisopropylethylamine) (2.06 g, 15.94 mmol) at 0° C. After 20 min, (R)-2-methyl-N—((S)-1,1,3,3-tetrafluoro-2-(2-fluorophenyl)-4-oxo-butan-2-yl)propane-2-sulfinamide (2.85 g, 7.97 mmol) in acetonitrile (10 mL) was added dropwise to the mixture at 0° C. and the mixture was stirred at 25° C. for 17.5 hours. The reaction mixture was concentrated to remove acetonitrile, water (50 ml) was added and extracted with ethyl acetate (200 ml). The organic layer was dried and evaporated. The crude product was purified by column chromatography (petrolium ether: ethyl acetate=5:1 to 4:1) to afford ethyl (S)-5-(((R)-tert-butylsulfinyl)amino)-4,4,6,6-tetrafluoro-5-(2-fluorophenyl)hex-2-enoate (1.77 g, 46.8% yield).