Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C([O:6][C:7]([C:9]1[S:10][C:11]([S:14][CH2:15][CH3:16])=[N:12][N:13]=1)=O)C>>[CH2:1]([NH:3][C:7]([C:9]1[S:10][C:11]([S:14][CH2:15][CH3:16])=[N:12][N:13]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)c1nnc(SCC)s1
Reactant: CCN
Product: CCNC(=O)c1nnc(SCC)s1
Temperature: 4 °C

Procedure:
54 g of an aqueous 50% ethylamine solution were added to 43.7 g of the compound obtained in Example 8(c), that is ethylthio-1,3,4-thiadiazole-2-carboxylic acid ethyester. This caused the temperature to rise to 46° C. The solution was subsequently heated to boiling point for another 15 minutes. It was then cooled to 4° C. and reacted with 50 ml icewater. The precipitated compound was removed by suction.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)CCc1nnn(Cc2ccccc2)c1O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nnn(Cc2ccccc2)c1O

Procedure:
1-Benzyl-4-(2-carboxyethyl)-5-hydroxy-1,2,3-triazole (5.0 g., 0.02 mol.) is suspended in 300 ml. of ethanol. Anhydrous hydrogen chloride gas is bubbled into the suspension for 30 minutes and the mixture is then heated on a steam bath for 20 minutes. The solution is cooled and evaporated to dryness to give a residue which is dissolved in 300 ml. of ethyl acetate. The ethyl acetate solution is washed with water, dried (MgSO4) and evaporated to dryness. Trituration with hexane containing a little acetone gives 1-benzyl-4-(2-carbethoxyethyl)-5-hydroxy-1,2,3-triazole.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.C(Cl)Cl.C(OCC)(=O)C>C1COCC1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@@H:12]([OH:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C[C@H](O)CC[C@]3(C)[C@H]1CC2
Yield: 48 %

Procedure:
These syntheses are depicted in FIG. 2. Androsta-4,16-dien-3-one (4) was reduced at -55° with lithium tris(1,2-dimethylpropyl)hydridoborate in THF (c) as described for the preparation of 2 (FIG. 1). Chromatography on silica gel with CH2Cl2 /ethyl acetate 9:1 gave pure axial alcohol 15 (48%, yield) and pure equatorial alcohol 6 (48% yield). Analytical samples were further purified by recrystallization (from PE at -30° for 5, from cyclohexane at RT. for 6).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:8][C:6]1[N:7]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3](=[O:9])[NH:4][CH:5]=1
Reactant: O=c1[nH]cc(Br)nc1Br
Reactant: C1COCCN1
Product: O=c1[nH]cc(Br)nc1N1CCOCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 3,5-dibromopyrazin-2(1H)-one (1.0 equiv.) in morpholine (5 equiv.) was heated to 100° C. for 24 h. Cooled to room temperature and filtered off the precipitate. The filtrate was partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and heptanes (0-50%). The pure fractions were concentrated to yield 5-bromo-3-morpholinopyrazin-2(1H)-one as a white solid in 43% yield. LCMS m/z (M+H)=259.9, Rt=0.41 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:26][CH2:27][O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:33]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:37][CH:36]=2)=[O:34])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCCCC3)cc2)cc1
Yield: 35 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]benzoic acid hydrochloride in 35% yield as an oil following radial chromatography (SiO2; gradient of 1-10% isopropanol in CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=4[CH:29]=3)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:30][CH:31]=2)=[CH:40][CH:41]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(C#Cc4ccc(C(C)(C)C)cc4)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-(tert-butyl)-phenylacetylene as a beige powder (65%). M1(ESI): 564.2. HPLC, Rt: 6.39 min (Purity: 98.9%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:29])=[CH:14][C:15]([O:27][CH3:28])=[CH:16][C:17]=3[C:18]32[C:24](=S)[S:23][C:22](=S)[NH:21]3)=[CH:9][CH:8]=1>CCO>[Br:6][C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:29])=[CH:14][C:15]([O:27][CH3:28])=[CH:16][C:17]=3[C:18]32[C:24]2=[N:5][CH2:1][CH2:2][CH2:3][N:4]2[C:22](=[S:23])[NH:21]3)=[CH:9][CH:8]=1
Reactant: COc1cc(F)c2c(c1)C1(NC(=S)SC1=S)c1cc(Br)ccc1O2
Reactant: NCCCN
Solvent: CCO
Product: COc1cc(F)c2c(c1)C1(NC(=S)N3CCCN=C31)c1cc(Br)ccc1O2
Temperature: 65 °C
Yield: 23.3 %

Procedure:
Propane-1,3-diamine (4.12 mL, 47.8 mmol) and 7′-bromo-4′-fluoro-2′-methoxyspiro[thiazolidine-4,9′-xanthene]-2,5-dithione (4.23 g, 9.56 mmol) were combined in 50 ml of EtOH and heated to 65° C. for 30 minutes. The solution was then concentrated. The product was purified via silica gel column chromatography (RediSep 330 g column) using 0-50% EtOAc in hexane to afford 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthene]-6(7H)-thione (1.0 g, 2.231 mmol) as an off white solid. MS m/z=448.0 [M+H].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24]Br)(=[O:19])[CH3:18]>CC#N>[Cl:3][C:4]1[N:5]([CH2:24][O:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Reactant: CC(=O)OCCOCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
NaH (0.12 g, 3.0 mmole, 60% oil dispersion) was added to a stirred suspension of 2,4,5,6,7-pentachlorobenzimidazole (14) (1.0 g, 3.4 mmole)in dry CH3CN (120 mL) under a N2 atmosphere. The solution was stirred until H2 evolution has ceased and a clear solution was obtained (20 min.). (2-Acetoxyethoxy) methyl bromide (0.68 g, 10.66 mmole) in CH3CN (34 mL) was then added dropwise. The reaction mixture was stirred for an additional 3 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil (165). The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions gave a solid which was recrystallized from MeOH to afford 1.39 g (72%) of 165: m.p. 119° C. 1H NMR (CDCl3): d 5.93 (s, 2H, C-1'), 4.143.92 (m, 4H, C-3' and C-4'), 1.83 (s, 3H, Ac). Anal. Calcd. for C12H9N2Cl5O3 : C,35.45; H, 2.23; N, 6.89. Found: C, 35.57; H, 2.17; N, 16.91.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:30][CH2:29][CH:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[NH:34][N:35]=2)[CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.O.CC(O)=O>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:30][CH2:29][CH:28]([C:31]5[N:32]=[C:33]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[NH:34][N:35]=5)[CH2:27]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: c1ccc(-c2nc(C3CCNC3)n[nH]2)nc1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A mixture of 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (300 mg, 0.95 mmol), 2-(5-pyrrolidin-3-yl-2H-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt (358 mg), triethylamine (0.32 mL) and AcOH (0.098 mL) in NMP (8.1 mL) was stirred overnight at room temperature. Sodium triacetoxyborohydride (222 mg) was added and the mixture stirred for 4 h. The mixture was diluted with water, filtered and the filtrate concentrated in vacuo. The residue was co-distilled with toluene and to give the crude product which was purified by preparative HPLC to give the title compound (50 mg).
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:17]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:25](OC)([O:28]C)[O:26]C.[NH4+].[OH-]>C1COCC1>[C:6]1([C:12]2[C:17]3[O:18][C:19]4[C:24]([B:25]([OH:28])[OH:26])=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1oc1c(-c3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
n-Butyllithium (13.51 mL, 33.8 mmol) was added dropwise to 4-phenyldibenzo[b,d]furan (3.3 g, 13.51 mmol) in 80 mL dry THF at −78° C. This reaction mixture was allowed to stir at room temperature for 5 hours and then cooled to −78° C. again. Trimethyl borate (4.52 mL, 40.5 mmol) was added slowly to the reaction. The reaction mixture was allowed to warm up to room temperature gradually over night with stirring. The mixture was poured into 50 mL of NH4OH solution with ice. The aqueous mixture was extracted with 3×80 mL ethyl acetate and dried over sodium sulfate, and the organic layer was evaporated to get yield 3.3 g (85%) product, which was used without purification and was confirmed by NMR.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[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][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:2]1([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:31])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCN
Product: NCCCCCCCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 22 g of mannose and 40 g of octadecylamine.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:8]([CH3:22])[N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=2Br)[CH:6]=1)=[O:4].[CH2:33]([S:36]([O-:38])=[O:37])[CH2:34][CH3:35].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:8]([CH3:22])[N:7]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=2[S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cn(Cc2ccc(C#N)cc2Br)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)c1cc(C#N)ccc1Cn1cc(C(=O)NC)c(=O)c(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 110 °C

Procedure:
A mixture of preparation 25a (70 mg, 139 μmol), sodium 1-propylsulfinate (54 mg, 415 μmol), L-proline (20 mg, 174 μmol), CuI (7 mg, 37 μmol), K2CO3 (24 mg, 174 μmol) in DMSO (0.7 mL) is heated 60 min at 110° C. The reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 11 mg (15% of theory); ESI mass spectrum: [M+H]+=532; Retention time HPLC: 1.06 min (Z003—001).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])C)([CH3:3])C.[Li]CCCC.[CH3:13][C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]=1.CSC1CCCN=1>C1COCC1>[N:4]1[CH2:1][CH2:3][CH2:7][C:5]=1[CH:13]=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1
Reactant: CC1=NCCCC1
Reactant: CC(C)NC(C)C
Agent: CSC1=NCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C1CCCCN1)C1=NCCC1
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (6.32 g, 62.52 mmol) in THF (100 mL) was dropwise added n-BuLi (2.89 M, 21.63 mL, 62.52 mmol) at −78° C. under nitrogen. Once all the n-BuLi was added, the temperature was adjusted to −5° C., and the reaction mixture was stirred for 30 min. Then a solution of 2-methyl-3,4,5,6-tetrahydropyridine (3.76 g, 38.70 mmol) in THF (15 mL) was added dropwise to the reaction mixture at −5° C., and then stirred. After 30 min, 2-methylthio-1-pyrroline (3.43 g, 29.77 mmol) was added dropwise over 30 min at −78° C. The reaction mixture was stirred as the temperature was allowed to gradually rise to room temperature, and was continuously stirred at room temperature overnight. THF solvent was removed under reduced pressure, then 30 mL of methanol was added dropwise to the residue. After removing all of the volatile solvent, pentane (2×50 mL) was added to the residue, and the mixture was filtered. Concentration of the filtrate under reduced pressure, followed by vacuum distillation (75° C. at 185 mTorr) delivered 4.1 g of product (84%). 1H NMR (CD2Cl2, 500 MHz): δ 9.64 (s, br, 1H), 4.48 (s, 1H), 3.78 (t, 2H, J=7.3 Hz), 3.27 (t, 2H, J=6.1 Hz), 2.45 (m, 2H), 2.33 (t, 2H, J=6.2 Hz), 1.73 (m, 4H), 1.67 (m, 2H). 13CNMR (CD2Cl2, 125 MHz): δ 173.6, 155.8, 86.5, 60.0, 41.7, 37.9, 29.5, 23.8, 22.7, 21.3.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([O-:11])(=[O:10])=O.[CH3:12]I>>[CH3:12][N:5]1[CH:6]=[CH:7][NH:2][C:3](=[S:8](=[O:10])=[O:11])[CH2:4]1
Reactant: O=S(=O)([O-])c1cnccn1
Reactant: CI
Agent: [Na+]
Product: CN1C=CNC(=S(=O)=O)C1

Procedure:
4.0 g of Pyrazine-2-sulfonic acid sodium salt (1900) was added to a solution of 20 ml methyl iodide/40 ml methanol and the mixture refluxed for 7 days. The solvent was evaporated and the residue chromatographed (Biogel P-2/water) giving 3.5 g of product (2000) which was recrystallized from ethanol/water, m.p. 270°-2° (dec). UV H2O max: 282 (3.86).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([O:16]CC)(=S)[C:12]([NH2:14])=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:11](=[O:16])[C:12]([NH2:14])=[N:10]2
Reactant: CCOC(=S)C(N)=O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: Nc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 25 °C
Yield: 20 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 4,5-dichloro-1,2-phenylenediamine (354 mg, 2.00 mmol; Aldrich Co.) and ethyl thiooxamate (333 mg, 2.50 mmol; Aldrich Co.) in 5 mL of ethanol was heated to reflux. The resulting brown solution was stirred under reflux for 10 h. The resulting brown suspension was cooled down to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 92 mg (20%) of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one: mp dec.>350° C. 1H NMR (300 MHz, DMSO-d6) δ 12.261 (br s, 1H, NH), 7.421 (s, 1H, H-5), 7.252 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O (M+) M/z 228.9810, found 228.9820.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: BrCc1ccccc1Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cc2ccccc2)CCCC1=O
Reaction time: 0.05 h
Yield: 36.5 %

Procedure:
40% Methanolic Triton B (0.95 mL, 2.1 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (510 mg, 2.1 mM) in 30 mL of DMF at −10° C. After 3 minutes, 2-benzylbenzyl bromide (548 mg, 2.1 mM) was added and the resultant mixture stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate and 1 N HCl, washed twice with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The reside was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 324 mg (36%) of the 9-[(2-benzylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.45-7.0 (m, 10H), 6.9 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.2 (s, 2H), 4.15 (s, 2H), 4.05 (s, 3H), 2.5 (m, 4H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1466, 1443, 1411, 1283, 1200, 1119, and 749. MS (ES) m/e 422, 424.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[C:11](=[N:13]\[OH:14])\[NH2:12])[N:6]=1.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[C:11]2[NH:12][C:26](=[O:27])[O:14][N:13]=2)[N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=N\O)/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of (1Z,2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (3 g, 10.29 mmol, 1 eq.) in DMF (50 ml) was added CDI (1.66 g, 10.29 mmol, 1 eq.) and stirring at room temperature was allowed for 30 min before heated to 80° C. for 6 h. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was triturated in MeCN and a white solid was isolated by filtration giving 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (2.89 g, 50% purity, 43% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1.[O:34]=[C:35]([CH3:39])[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:13][CH:12]=2)=[C:4]([N:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:36](=[O:37])[C:35](=[O:34])[CH3:39])[CH:3]=1
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reactant: CC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)NCC(C)(C)O)cc1
Temperature: 120 °C

Procedure:
To 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propyl]-N-(2-hydroxy-2-methylpropyl)-benzenesulfonamide (0.138 g) in toluene (10 mL) was added 2-oxopropionyl chloride (0.3 mL), and the mixture heated at 120° C. for 3 h to form N-(5-chloro-2-{3-[4-(2-hydroxy-2-methylpropylsulfamoyl)-phenyl]-propionyl}-phenyl)-2-oxo-N-phenyl-propionamide, which was used without further purification.
Reaction SMILES: C(OC)(=O)CC(C)=O.Cl.C(NN)(C)C.[CH:15]1([C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[N:21]=[CH:20][C:19]=2[CH:26]=[O:27])CC1>>[CH:23]([N:22]1[C:18]([CH3:15])=[C:19]([CH:26]=[O:27])[CH:20]=[N:21]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: CC(C)NN
Agent: COC(=O)CC(C)=O
Agent: Cl
Product: Cc1c(C=O)cnn1C(C)C

Procedure:
1-Isopropyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with methyl acetoacetate and isopropyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(#N)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:38]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)c4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
1,8 Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride in acetonitrile (100 mL). The mixture was stirred for 30 minutes. 3-Chlorobenzoyl chloride (0.6 g, 3.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred with CH2Cl2 (60 mL) and 2N HCl (30 mL). The mixture was filtered and the solid was slurried with ethanol (20 mL) to give 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.8 g, 96%) as a white solid: mp 266-268° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.37-2.66 (m, 2H), 2.86-2.99 (m, 1H), 4.48 (d, J=17.3 Hz, 1H), 4.53 (d, J=21.1 Hz, 1H), 4.55 (s, 2H), 5.12-5.20 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.48-7.66 (m, 5H, Ar), 7.87 (d, J=7.7 Hz, 1H, Ar), 7.93 (d, J=1.3 Hz, 1H, Ar), 9.23 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.60, 31.20, 39.66, 46.28, 51.60, 121.76, 126.07, 127.08, 128.38, 130.40, 130.77, 131.22, 131.65, 133.23, 134.37, 136.01, 140.21, 164.94, 168.07, 171.04, 172.88; Anal. calcd. for C21H18N3O4Cl: C, 61.24; H, 4.41; N, 10.20; Cl, 8.61. Found: C, 60.92; H, 4.21; N, 10.01; Cl, 8.92.