Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH:27]([CH3:31])[CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]([CH3:31])[CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C(C)CCBr
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Yield: 109.2 %

Procedure:
A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)butyl bromide (4.25 g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 8.01 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 3:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 7.21 grams (98%) of a viscous yellow oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C@@:12]([OH:19])([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C@@:12]([OH:19])([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=[O:14]
Reactant: CC(C)(C)[C@@](C)(O)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@](C)(O)C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethylsulfoxide (2,578 ml. 36.3 mmol) in methylene chloride (3 ml) was added dropwise at -78° C. to a stirred solution of oxalyl chloride (1.585 ml, 18.2 mmol) over 5 minutes and stirred at -78° C. for 10 minutes. A solution of (R)-2,3,3-trimethyl-1,2-butanediol in methylene chloride (25 ml) was added dropwise and stirred for 15 minutes at -78° C. Triethylamine (11.51 ml, 82.6 mmol) was added and the reaction was allowed to come to room temperature. The mixture was diluted with additional methylene chloride, washed with 10% sulfuric acid, the combined aqueous phase was extracted with methylene chloride, and the combined organic layer was washed with saturated sodium bicarbonate, dried (magnesium sulfate), and concentrated by distillation at atmospheric pressure to afford 2.15 g of (R)-2,3,3-trimethyl-2-hydroxybutanal as a pale gummy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=[NH:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[N:24]=[C:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([OH:11])[CH:7]=2)[N:1]=1)=[O:28])[CH3:20]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: CCOC(=N)C(=O)OCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(O)c2cc(O)ccc2n1
Temperature: 60 °C

Procedure:
2-amino-5-hydroxy-benzoic acid (15 mmol) are suspended in ethanol (water free, 600 ml) and heated up to 60° C. and stirred. Then triethylamine (30 mmol) is added and a clear solution is formed. Ethoxy-imino-acetic acid ethyl ester (16.5 mmol) is added at 60° C. and after 15 minutes another portion of triethylamine (15 mmol) is added and the mixture stirred for another 30 minutes. The mixture is cooled down to RT and left at RT without stirring over night. The solid material formed was filtered off, washed with ethanol/ether and dried (vacuum). A pale brown powder with mp. 258-260° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.95 min; [M+H]+=395.14.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.Cl[S:12]([C:15]1[N:23]=[C:22]2[N:17]([C:18]([O:25][CH3:26])=[N:19][C:20]([CH3:24])=[CH:21]2)[N:16]=1)(=[O:14])=[O:13].[NH2:27][C:28]1[C:29]([C:36]([F:39])([F:38])[F:37])=[N:30][N:31]([CH2:34][CH3:35])[C:32]=1[CH3:33]>C(#N)C>[CH2:34]([N:31]1[C:32]([CH3:33])=[C:28]([NH:27][S:12]([C:15]2[N:23]=[C:22]3[N:17]([C:18]([O:25][CH3:26])=[N:19][C:20]([CH3:24])=[CH:21]3)[N:16]=2)(=[O:14])=[O:13])[C:29]([C:36]([F:38])([F:37])[F:39])=[N:30]1)[CH3:35]
Reactant: CCn1nc(C(F)(F)F)c(N)c1C
Reactant: COc1nc(C)cc2nc(S(=O)(=O)Cl)nn12
Solvent: CC#N
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)nc(OC)n3n2)c1C
Reaction time: 18 h

Procedure:
Pyridine (0.32 g (4.0 mmol)) and dimethyl sulfoxide (0.03 g (0.4 mmol)) were added to a solution of 1.0 g (4.0 mmol) of 2-chlorosulfonyl-5-methoxy-7-methyl[1,2,4]triazolo[1,5-c]pyrimidine and 0.77 g (4.0 mmol) of 4-amino-1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 15 mL of acetonitrile at ambient temperature with stirring. After 18 hours, the volatiles were removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane and water, stirring for 10 min before separation. The solids were recovered by filtration and washed with ether. They were then resuspended in water and the mixture stirred for 30 min. The solids were recovered by filtration, washed with ether, and dried under reduced pressure at 40° C. overnight. The resulting 1.3 g (78 percent of theory) of white powder melting at 208°-209° C. was the title compound (Compound 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N(c1cc(Br)cnc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 51.6 %

Procedure:
To a solution of 5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol) in pyridine (2.41 ml) was dropwise added benzenesulfonyl chloride (0.851 g, 4.82 mmol) at 0° C. The mixture was stirred for 40 min at room temperature and acidified with 1 N HCl. The residue was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give N-(5-bromo-2-chloropyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide (0.606 g, 26% yield) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.02 (1H, s), 7.47-7.56 (2H, m), 7.59-7.66 (1H, m), 7.78-7.86 (2H, m), 8.16 (2H, dd, J=2.4, 7.2 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([S:36]([CH3:38])=[O:37])=[N:34]2)=[CH:29][CH:28]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:38][S:36]([C:33]1[N:32]=[CH:31][C:30]2=[CH:29][CH:28]=[C:27]([C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)[N:35]2[N:34]=1)=[O:37]
Reactant: OB(O)c1cccnc1
Reactant: CS(=O)c1ncc2ccc(Br)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Into a round bottom flask, Palladium Acetate (0.052 g, 0.00023 mol) and Triphenylphosphine (0.076 g, 0.00029 mol) were dissolved in dioxane (3.5 mL, 0.043 mol) and the mixture was allowed to stir at room temperature for 10 minutes. DMF (5 mL), 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.300 g, 0.00115 mol) was then added and the reaction was again allowed to stir for 10 minutes. [B] 3-Pyridylboronic acid (0.284 g, 0.00231 mol) was added followed by 0.9 M of Sodium carbonate in water (1 mL, 0.001 mol) and Ethanol (3.5 mL, 0.060 mol). The reaction mixture was then heated at 80° C. overnight. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over sodium sulfate. The solid was filtered and washed. The solvent was removed under vacuum. The reaction mixture was purified by ISCO column chromatography with DCM and methanol as eluant (0 to 10%). The collected fractions afforded 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.19 g, 61%). LCMS (E/I+) 259.8 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:19](Cl)(=[O:21])=[O:20])[C:5]([C:8]2[C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>[N+](C)([O-])=O>[C:27]1([S:19]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[S:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:17])=[O:16])(=[O:21])=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=S(=O)(c1ccccc1)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)c1ccccc1
Temperature: 100 °C
Yield: 74 %

Procedure:
Inside a glove box, a 125 mL round-bottom flask equipped with a stirring bar, reflux condenser, and gas inlet was charged with 4,4′-dibromobiphenyl-2,2′-disulfonyl dichloride (10.18 g, 20 mmoles) and aluminum chloride (5.87 g, 44 mmoles). Benzene (14 mL) and anhydrous nitromethane (40 mL) were added and the mixture stirred until dissolved. The solution was heated to 100° C. for about 8 hours. The solution was cooled to room temperature and poured onto 200 g ice mixed with 100 mL hydrochloric acid. The mixture was extracted several times with dichloromethane. The organic extracts were washed twice with water, dried with sodium carbonate, filtered, and evaporated to give 11.75 g (99%). The mixture was purified by column chromatography using silica gel and dichloromethane (Rf 0.32) to give 8.73 g (74% yield) of 2,2′-bis-benzenesulfonyl-4,4′-dibromobiphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:27])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[CH2:7]1.[OH-].[Na+].Cl>CO.O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[S:18][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CSc1nc(C(=O)O)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (850 mg) of (1-4) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), 1 mol/L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid was added to the reaction mixture, and the organic solvent alone was evaporated under reduced pressure. Saturated brine was added to the obtained residue, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (479 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][NH2:20])=O.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:11][C:17]([C:13]3[S:12][CH:16]=[CH:15][CH:14]=3)=[N:19][N:20]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NNC(=O)c1cccs1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nnc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
3-amino-6-bromo-pyrazine-2-carboxylic acid (3.2 g, 14.68 mmol) and thiophene-2-carbohydrazide (2.152 g, 14.68 mmol) were suspended in acetonitrile (48.00 mL) at room temperature and dibromo(triphenyl)phosphorane (24.79 g, 58.72 mmol) was added, followed byadditional acetonitrile (16.00 mL). The reaction mixture turned bright yellow in colour and was stirred at room temperature for 1 h. After this time, the reaction mixture cooled in an icebath and DIPEA (7.209 g, 9.716 mL, 55.78 mmol) was added dropwise. The reaction mixture was stirred in the ice bath for 1 h and then additional DIPEA (2.277 g, 3.069 mL, 17.62 mmol) added and the reaction mixture stirred for left for 30 mins and further DIPEA (1.897 g, 2.557 mL, 14.68 mmol) added. The reaction mixture was stirred for 1 h and then filtered. The solid was washed with ether, isolated and then triturated with acetonitrile and washed with ether to give the product as a yellow solid (2.776 g, 57% yield); 1H NMR (400.0 MHz, DMSO) 7.35 (s, 1H), 7.80 (br s, 2H), 7.98 (m, 1H), 8.04 (m, 1H) and 8.45 (s, 1H); MS (ES+) 326.04
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:4]=1.[OH-].[K+].C(O)(=[O:28])C>CS(C)=O.O>[O:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([C:5]3[NH:4][C:3](=[O:28])[N:8]4[CH:9]=[CH:10][N:11]=[C:7]4[CH:6]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CC(=O)O
Reactant: CSc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Yield: 95.3 %

Procedure:
4-(4-(5-(methylthio)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.4000 g, 1.225 mmol) and potassium hydroxide (1.021 mL, 6.127 mmol) were suspended in DMSO (3 mL) and heated at 100° C. for 1.5 hours in a microwave. The reaction mixture was diluted with water (40 mL) and acidified with acetic acid (1.052 mL, 18.38 mmol). The resulting solids were collected by filtration and dried under high vacuum to afford 7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (0.3460 g, 95.28% yield). MS (apci) m/z=297.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[C:29]([S:30]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and 2-chloro-pyridine-3-sulfonyl chloride. White solid. MS (ESI): 490.2 (MH+)
Reaction SMILES: [ClH:1].CO[C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][NH2:10])[NH2:6].Cl.[S-:13][C:14]#[N:15].[K+].C(O)C>O>[ClH:1].[NH2:10][CH2:9][CH2:8][CH2:7][C:5]1[NH:6][C:14](=[S:13])[NH:15][CH:4]=1
Reactant: N#C[S-]
Reactant: COC(=O)[C@@H](N)CCCN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCCCc1c[nH]c(=S)[nH]1
Temperature: 5 °C

Procedure:
To an Erlenmeyer flask was prepared a solution of L-ornithine methyl ester hydrochloride (10.50 g, 47.9 mmol) in water (125 mL). The solution was cooled to 5° C. and pH adjusted to a value of 1.5 with concentrated HCl. While being careful to maintain the above stated temperature and pH, 5% Na(Hg) (250 g) was added slowly to the solution over a time period of 35 min. After the addition was complete and bubbling had calmed the Hg was decanted from the solution. The remaining aqueous portion was drained into a separate flask where potassium thiocyanate (14.0 g, 144 mmol) and water (75 mL) was added. The pH of solution was adjusted to a value of 4.30 and the flask was then heated at 95° C. while open to the atmosphere for 1.5 h. After cooling to room temperature, ethanol (75 mL) was added and the reaction was evaporated to dryness. The residue was taken up in methanol and filtered to remove NaCl. After all of the NaCl had been removed the crude residue was purified by column chromatography (CH2Cl2/MeOH sat. with NH3 80:20) to afford the desired compound in its free base form. Addition of concentrated hydrochloric acid to a methanol solution (50 mL) of the free base followed by evaporation to dryness gave 4.51 g (48%) of the title compound 42 as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 11.69 (s, 1H), 7.77 (s, 2H), 6.58 (s, 1H), 2.73 (m, 2H), 2.42 (t, 2H, J=6.6 Hz), 1.76 (tt, 2H, J=7.5, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.23, 128.03, 111.69, 38.08, 25.75, 21.27; HRMS (FAB) calcd for C6H12N3S (MH+) 158.0752. found 158.0743.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]/[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: O=CC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
As in Example 99, 3,3-bis(4-chlorophenyl)-2-propenal (11.08) was reacted with (carbethoxymethylene)triphenylphosphorane (14.3 g) in ethanol (30 ml) for 30 minutes at ambient temperature. The mixture of esters obtained from the usual work up was purified by crystallization from ether-hexane to give 8.1 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester, mp 98°-100° C. A portion of the (E)-isomer was crystallized from hexane to yield the pure ester (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester mp 98.5°-100° C.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(CCO)cc1
Product: Cc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 89.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (275 mg, 1.09 mmol) prepared in Example 1 (1a) and 2-(4-methylphenyl)ethanol (159 μL, 1.14 mmol) to give 306 mg of the title compound (colorless crystalline solid, yield: 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:3]1=2.O1C2C=C(O)C=CC=2CC1.[F:23][C:24]([F:43])([F:42])[C:25]1[O:29][C:28]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])=[CH:27][CH:26]=1.ClC1C=CC=C2C=1N(C(C1C=CC=CC=1)C1C=CC=CC=1)C(=O)C2=O>>[OH:40][C:33]1([C:10]2[C:9]([OH:12])=[CH:8][C:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]=3[CH:11]=2)[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:31]([CH2:30][C:28]2[O:29][C:25]([C:24]([F:42])([F:23])[F:43])=[CH:26][CH:27]=2)[C:32]1=[O:41]
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Reactant: CN1CCOc2cc(O)ccc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21
Agent: Oc1ccc2c(c1)OCC2
Product: CN1CCOc2cc(O)c(C3(O)C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 21B, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace 2,3-dihydrobenzofuran-6-ol, and 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione to replace 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (56%) as a colourless powder: mp 184-186° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.63 (s, 1H), 7.24-7.18 (m, 2H), 7.13 (s, 1H), 7.00-6.90 (m, 3H), 6.59 (d, J=3.3 Hz, 1H), 6.50 (s, 1H), 6.03 (s, 1H), 4.99 (s, 2H), 4.20 (t, J=4.1 Hz, 2H), 3.14-3.09 (m, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 153.8, 145.8, 144.1, 142.8, 139.3 (q, J=42 Hz), 132.7, 128.9, 128.5, 123.7, 122.2, 119.6, 119.1 (q, J=266 Hz), 114.1, 112.3, 109.1, 108.3, 103.1, 74.7, 64.9, 49.2, 39.4, 36.4; MS (ES+) m/z 461.2 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]=[CH:27][N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](=[O:49])[N:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]3[N:26]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=4)[CH:27]=[N:28][CH:29]=3)=[CH:20][N:19]=2)[CH:17]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 5-hydroxymethyl-pyridine-2-carbonitrile from step 3 (37 mg, 0.28 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (150 mg, 0.28 mmol) in CH2Cl2 (1.38 ml) was added DIEA (106 μl, 0.61 mmol) followed immediately by the addition of Tf2O (70 μl, 0.41 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (1.38 ml) and heated to 60° C. for several hours. The MeOH was removed in vacuo and the residue treated with saturated NaHCO3 (2 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine (1×10 mL), dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.