Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:22]([CH3:29])[C:23]([CH3:28])([CH3:27])[C:24](=O)[N:25]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:22]([CH3:29])[C:23]([CH3:28])([CH3:27])[C:24](=[S:40])[N:25]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: Cc1c(C2=NC(=O)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(C2=NC(=S)C(C)(C)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 74.2 %

Procedure:
To a solution of compound 6 (98 mg, 0.22 mmol) in toluene (5 mL) was added Lawesson's reagent (150 mg, 0.37 mmol) in one portion. The resulting mixture was heated at 60° C. for 4 h, then poured into ice water. The resulting mixture was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with water, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with hexanes/ethyl acetate (7:3) to give the desired thioketone 21 (78 mg, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 1H), 7.32 (d, 2H), 7.28 (dd, 1H), 7.22 (d, 1H), 7.08 (d, 2H), 3.62 (s, 3H), 2.48 (s, 3H), 1.55 (s, 6H); ESMS m/z: 477.0 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O>[C:16]([S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(Sc1ccccc1C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
2-Mercapto-benzoic acid (1.5 g, 9.73 mmol) was dissolved in a solution of NaHCO3 (2.6 g, 0.031 mol) in H2O (25 mL). The 2-mercapto-benzoic acid solution was cooled to 0° C. Benzoyl chloride (1.36 g, 9.73 mmol) was then added followed by additional Na2CO3 (2.01 g, 14.60 mmol). The reaction mixture was stirred for 30 min at 0° C. and then, after allowing it to warm to room temperature, the reaction mixture was allowed to stir for an additional 45 minutes. Subsequently the reaction mixture was acidified with concentrated HCl forming a white precipitate. The precipitate was collected washed with cold water and dried in a vacuum dessicator overnight to yield the title compound in 83% yield (2.08 g, 8.08 mmol).
Reaction SMILES: [CH3:1]I.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][CH3:25])[C:10](=[O:26])[C:9]2([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][C:29]=1[Cl:36])[CH3:27]>O1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][CH3:25])[C:10](=[O:26])[C:9]2([C:28]1[CH:33]=[C:32]([CH2:34][O:35][CH3:1])[CH:31]=[CH:30][C:29]=1[Cl:36])[CH3:27]
Reactant: CI
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(CO)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.08 ml of methyl iodide and then, at 0° C., 0.02 g of sodium hydride as a 60% suspension in oil are added to 0.2 g of the compound of Example 140 in 2 ml of tetrahydrofuran. After stirring for 16 hours at room temperature, the reaction mixture is hydrolysed with a 5% aqueous ammonium chloride solution and extraction is carried out with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate. The solvents are evaporated under reduced pressure. The product is obtained after crystallization from n-pentane; M.p.=122° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[N:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)nc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ncccc2Br)nc1
Reaction time: 18 h

Procedure:
3-Bromo-2-chloropyridine (7.27 g, 37.8 mmol), 5-aminopyridin-2-ol (4.99 g, 45.3 mmol), freshly ground cesium carbonate (36.9 g, 113 mmol), and DMSO (37.8 ml, 37.8 mmol) were added into a glass round bottom pressure vessel equipped with a stir bar. The vessel was sealed and placed in a preheated oil bath at 130° C. After 18 h, the reaction was diluted with EtOAc (4×250 mL) and the whole solution was sonicated. After the solid was settled, the top solution was decanted through a pad of celite and silica gel (each layer was 1 cm). This procedure was repeated for the salt residue which left in the flask to remove the product and DMSO from the salt. The filtrate was concentrated to give an oil which included the product and DMSO. The product was extracted with EtOAc (3×300 mL) and DCM (1×100 mL). The EtOAc and DCM layers were washed separately with a minimum amount of brine. The organic phases were dried separately over a minimum amount of MgSO4. The MgSO4 was filtered off and the filtrates were combined and concentrated. A wet, light green solid was obtained. The solid was triturated with hexanes. The solid was filtered off, collected, and dried under vacuum. The product, 6-(3-bromopyridin-2-yloxy)pyridin-3-amine was collected as tan solids. A second batch was obtained from the filtrate. The filtrate was concentrated to give an oil. The oil was purified by ISCO column chromatography using 90:10 DCM:(90:10:1 DCM:MeOH:NH4OH). A light yellow solid, was obtained, dried under vacuum, and given a sample ID: A wet, green solid was obtained, dried under vacuum. MS Calcd for C10H8BrN3O: [M]+=265. Found [M+1]+=266.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[OH:16])[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])=[C:20]([Cl:31])[CH:19]=1)=[O:5])[CH3:2].CC1C=CC(S(O[CH2:43][C@H:44]2[CH2:46][O:45]2)(=O)=O)=CC=1>>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:43][C@H:44]1[CH2:46][O:45]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])=[C:20]([Cl:31])[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: CCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Yield: 47.4 %

Procedure:
The title compound (235.4 mg, 0.474 mmol, 47.4%) was obtained as light yellow crystals from N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide) (440.9 mg, 1.00 mmol) and (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2>CN(C)C=O.C(O)(=O)C.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Sc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Sc3ccccc3)[C@H]1S2
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(phenylthio)carbonylaminopenam-3-carboxylate (1.04 g.) in a mixture of dimethylformamide (7 ml.) and acetic acid (2.2 ml.) was added zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1.5 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into a mixture of ethyl acetate (30 ml.) and ice-water (30 ml.) containing 2% hydrochloric acid (2 ml.), extracted and then the aqueous layer was further extracted with ethyl acetate (10 ml.) The combined extract was washed with water and a saturated sodium chloride aqueous solution in turn, dried over magnesium sulfate and then the solvent was removed under reduced pressure. The obtained residue was crystallized by adding a small amount of acetonitrile to give 2-methyl-2,3-methylene-6-(phenylthio)carbonylaminopenam-3-carboxylic acid (0.43 g.), mp 116° to 119°C (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask were placed a solution of 2,4-dihydroxy-6-methylbenzaldehyde (2.0 g, 13.16 mmol, 1.00 equiv) in dichloromethane (50 mL), 3,4-dihydro-2H-pyran (1.65 g, 19.64 mmol, 1.49 equiv) and pyridinium p-toluenesulfonate (330 mg, 1.31 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature. Then it was diluted with 100 mL of dichloromethane and washed with 3×20 mL of 1 M sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.8 g (52%) of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:22])=[CH:5][C:6](=[C:8]([C:20]#[N:21])[C:9]([O:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])[CH:7]=1>C(N)CCC>[CH2:20]([N:21]1[C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:20]#[N:21])[C:9]([O:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])[CH:5]=[C:4]1[CH3:22])[CH2:8][CH2:6][CH3:5]
Reactant: CCCCC(CC)COC(=O)C(C#N)=C1C=C(C)OC(C)=C1
Solvent: CCCCN
Product: CCCCC(CC)COC(=O)C(C#N)=C1C=C(C)N(CCCC)C(C)=C1
Yield: 128.3 %

Procedure:
A solution of 0.30 g (1 mmol) of 2-ethylhexyl (2,6-dimethyl-pyran-4-ylidene)cyanoacetate (prepared as described in example 1) in 4 ml butylamine was refluxed at 80° C. for 1 h under nitrogen. Removal of the excess of butylamine at reduced pressure left a orange oil which was purified by FC (n-hexane/EtOAc 1:1) yielding 0.23 g (64%) of 2-ethylhexyl (1-N-butyl-2,6-dimethyl-1H-pyridin-4-ylidene)cyanoacetate as a slightly yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][P:5](Cl)([CH3:7])=[O:6].C1[O:15]C1C>C(O)C.O>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][P:5]([CH3:7])(=[O:15])[OH:6]
Reactant: CC1CO1
Reactant: CP(=O)(Cl)CC[C@H](N)C(=O)O
Solvent: CCO
Solvent: O
Product: CP(=O)(O)CC[C@H](N)C(=O)O
Reaction time: 24 h
Yield: 81 %

Procedure:
0.33 g (0.0015 mol) of L-homoalanin-4-yl(methyl)phosphinic acid chloride are dissolved in 15 ml of ethanol/water and mixed with 0.3 g (0.005 mol) of propeneoxide. After allowing to stand for one day at room temperature, 0.22 g (80.1% of theory) of L-homoalanin-4-yl(methyl)phosphinic acid is obtained as a white solid with a melting point of 212°-214° C. (decomposes); [α]D22 =14.7° (c=0.984 in H2O).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1COCC1.ClCCCl.N1C=CC=CC=1.Cl.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32]>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN(C)CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 296.1 %

Procedure:
To a solution of 4-fluoro-3-nitroaniline (2.48 g, 15.9 mmol) in 1:1 THF/DCE (200 mL) was added pyridine (7.54 g, 95.4 mmol, Aldrich), 2-dimethylaminoacetyl chloride hydrochloride (0.66 g, 4.20 mmol, Lancaster), and catalytic DMAP (˜0.100 g). After heating at 65° C. for 1.5 hrs, the crude reaction mixture was diluted with dichloromethane (300 mL), washed with saturated NaHCO3 (50 mL), evaporated, and purified by column chromatography (dichloromethane to 5% methanol/dichloromethane) to provide N1-(4-fluoro-3-nitrophenyl)-N2,N2-dimethylglycinamide (3.0 g, 78%) as a brown solid. ESIMS (M+H)+=242.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:34]=1[NH2:35]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][C:5]([C:6]([NH:35][C:34]2[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:33]=2[CH3:32])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.9 %

Procedure:
To 4-chloro-2-methoxy-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride (70 mg, 0.19 mmol) in DCM (0.5 mL) were added triethylamine (39 μL, 0.28 mmol) and 2,6-dimethylaniline (28 μL, 0.22 mmol). The mixture was stirred at rt for 12 hrs and was purified via a prep TLC plate eluting with ethyl acetate in hexane (30%) to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide (55.0 mg). MS [M+H]+ 460.2; tR=2.85 min (method 1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[CH:4][C:3]=1[S:12][CH3:13].[B-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:11][CH2:9]2)=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: CSc1cc(C(=O)CBr)ccc1C
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: CSc1cc(C2CO2)ccc1C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 18 g of 4'-methyl-3'-methylthio-2-bromoacetophenone and 300 ml of methanol was gradually added 8 g of sodium borohydrate and thereafter the mixture was stirred for one hour at 40°-50° C. After distilling off methanol from the reaction mixture, 200 ml of water was added to the residue and the product was extracted with 300 ml of benzene. Then, benzene was distilled off and the residue formed was purified by a silica gel column chromatography (eluant: benzene) to provide 8.5 g of oily 4-methyl-3-methylthiostyrene oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52](O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)=[O:53]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccsc5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1OC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 48 (150 mg, 0.33 mmol), EDCI (130 mg, 0.66 mmol) and DMAP (20 mg, 0.16 mmol) and pyridine (0.13 ml, 1.65 mmol) in CH2Cl2 (4 ml) was added 3,4-dimethoxybenzoic acid (120 mg, 0.66 mmol) at room temperature and stirred for 16 hours. The reaction mixture was diluted with CH2Cl2 (8 ml), and washed with brine (8 ml). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (C18) to provide the titled compound (55 mg, 27%).
Reaction SMILES: [CH:1]([C:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)=O.C(N)CCC.[N+:19]([CH3:22])([O-:21])=[O:20]>C1(C)C=CC=CC=1>[C:8]1([N:5]2[CH2:6][CH:7]=[C:3]([CH:1]=[CH:22][N+:19]([O-:21])=[O:20])[NH:4]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=CC1=NN(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: O=[N+]([O-])C=CC1=CCN(c2ccccc2)N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 3-formyl-1-phenyl-2-pyrazoline (3.48 g), n-butylamine (0.2 ml) and nitromethane (10 ml) was stirred at 100° C. for 1 hour, then was cooled to room temperature. The resultant dark red crystalline mass was dissolved in toluene and was eluted down a silica column with toluene. The major orange fraction was evaporated to dryness under reduced pressure and the residue was recrystallised from ethanol to give a 59% yield of dark red micro crystals (MP 150° C.).
Reaction SMILES: [N:1]1[NH:2][C:3]([NH2:6])=[CH:4][CH:5]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:13]=1[Cl:14]>C(O)(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[C:17]([C:18]([F:21])([F:19])[F:20])[N:2]3[N:1]=[CH:5][CH:4]=[C:3]3[N:6]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccn[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2ccnn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2H-pyrazol-3-ylamine (4.0 g, 48 mmol) and 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (11.4 g, 40 mmol) in acetic acid (80 mL) was heated at reflux for 4 h. The solution was poured into ice-cold 10% aqueous ammonia and the mixture was stirred at 0° C. for 0.5 h. The solid was isolated by filtration, triturated with EtOH (40 mL), and dried to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine as a pale-yellow solid. MS (ISP) 332.1 [(M+H)+]; mp 130–131° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(OCC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M179) (266 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (175 mg, 85%).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[NH:5][C:4](=[O:6])[CH:3]2[CH2:7][CH2:8][CH2:9][N:2]12.[C:12]1([S:18][CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18][CH2:19][N:5]2[S:1](=[O:11])(=[O:10])[N:2]3[CH2:9][CH2:8][CH2:7][CH:3]3[C:4]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1NS(=O)(=O)N2CCCC12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: O=C1C2CCCN2S(=O)(=O)N1CSc1ccccc1
Yield: 65.8 %

Procedure:
To a mixture of tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (5.0 g, 28.4 mmol) suspended in 150 ml of toluene was added phenylthiomethyl chloride (6.76 g, 42.6 mmol) and tetrabutylammonium bromide (0.91 g) . The resulting mixture was refluxed for 6 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (25-30% ethyl acetate in hexane) to afford 5.58 g (66%) of 2-phenylthiomethyl-tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3(2H)_-one 1,1-dioxide (Formula VI: R1 =H; R2 and R3 together=--(CH2)3 --) as a solid, m.p. 90.5°-91.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:17])[C:13]([O:15]C)=[O:14])[C:3]([O:5]C)=[O:4]>Cl>[NH2:1][C@@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:17])[C:13]([OH:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)[C@@H](N)CCCCC[C@H](N)C(=O)OC
Agent: Cl
Product: N[C@@H](CCCCC[C@H](N)C(=O)O)C(=O)O
Reaction time: 12 h

Procedure:
The ester from step (b) was heated under reflux in 6M HCl (7.2 ml) for 2 hours under N2. The volatile compounds were evaporated. The residue was dissolved in water (5 ml), ethanol was added (20 ml) and slow addition of ether led to a white, crystalline precipitate. This mixture was kept for 12 hours in the refrigerator, filtered, washed with ether and dried under vacuum.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([CH2:7][P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])=[O:6].[I-].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][N+](C)(C)C)=[CH:16]1>CN(C=O)C.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH:7]([P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])[C:5]([O:4][CH3:3])=[O:6])=[CH:16]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C[N+](C)(C)Cc1c[nH]c2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1c[nH]c2ccccc12)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of indole (5.6 g, 47.8 mmol) in acetonitrile (130 ml) is added Eschenmoser's salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 min. The mixture is concentrated in vacuo and the residue is diluted with 1M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried over sodium carbonate and concentrated in vacuo to give 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) is dropped methyl iodide (5 ml, 80 mmol). The mixture is stirred at r.t. for 6 hrs. and concentrated in vacuo to give (3-indolylmethyl)trimethylammonium iodide as a brown foam. To a cooled (0° C.) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) is added trimethyl phosphonoacetate (6.7 ml, 41 mmol) and the mixture is stirred at 0° C. for 30 min. To the mixture is added (3-indolylmethyl)trimethylammonium iodide and the whole is stirred at r.t. overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate to give methyl 3-(3-indolyl)-2-(dimethylphosphono)propionate a a brown oil.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([NH:6][C:7](=[O:9])[O-:8])[CH3:5].[CH3:10][O:11][C:12]1[C:13](Br)=[CH:14][C:15]2[CH:16]([CH3:24])[CH:17]3[CH2:21][NH:20][CH2:19][CH:18]3[C:22]=2[CH:23]=1>CN(C=O)C.O>[CH2:4]([NH:6][C:7](=[O:8])[O-:9])[CH3:5].[CH3:10][O:11][C:12]1[C:13]([C:1]#[N:2])=[CH:14][C:15]2[CH:16]([CH3:24])[CH:17]3[CH2:21][NH:20][CH2:19][CH:18]3[C:22]=2[CH:23]=1
Reactant: COc1cc2c(cc1Br)C(C)C1CNCC21
Reactant: N#C[Cu]
Agent: CCNC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C#N)C(C)C1CNCC21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
CuCN (68 mg, 0.85 mmol) was added to a solution of N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (60 mg, 0.17 mmol) in DMF (1.7 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAC and H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MS calculated for C17H20N2O3+H: 301, observed: 301.