Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:23]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[NH:29])([O-:25])=[O:24]>C(O)C>[O:13]=[C:11]1[NH:30][C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[N+:23]([O-:25])=[O:24])=[N:29][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: N=C(N)c1ccccc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2[N+](=O)[O-])[nH]c1=O
Yield: 20.1 %

Procedure:
Diethyl ethoxymethylenemalonate (0.73 g., 3.44 mmoles), potassium carbonate (0.95 g., 6.88 mmoles), and ethanol (11 ml.) were added to 2-nitrobenzamidine hydrochloride (0.69 g., 3.44 mmoles)(prepared according to general method disclosed in U.S. Pat. No. 2,450,386). The mixture was heated under reflux for 3.5 hours. The cooled mixture was filtered. The filtrate was poured into ice-water (150 ml.) and the pH adjusted to 6.0 with acetic acid. The precipitate was collected and dried to give the title compound (0.20 g., 20.2%), m.p. 171°-175°. Recrystallization from acetonitrile gave analytical material, m.p. 175°-177°.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[F:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:10][C:11]1[N:16]=[CH:15][C:14]([N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Two reactions were set up in parallel. For each of them, to a solution of 5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 11.71 mmol) in dry dichloromethane (100 mL), (6-fluoro-3-pyridinyl)boronic acid (1.980 g, 14.05 mmol), copper(II) acetate (2.126 g, 11.71 mmol) and pyridine (1.420 mL, 17.56 mmol) were added. The reaction was left under stirring under air atmosphere at room temperature overnight. The two reaction mixtures were combined and the solid was filtered off. The resulting solution was washed with water (90 mL). The aqueous phase was extracted twice with dichloromethane (twice 90 mL). The organic phases were combined and washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent afforded a residue which was purified by silica gel chromatography (Biotage system, 100 g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 65/35 to 50/50 to afford the title compound as a white solid (1.27 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)c(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chloro-4-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.7 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([O:6][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CCC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a cooled solution of cyclopent-3-enol (30.40 g, 0.36 mol) in THF (300 mL) at 0° C. was added NaH (18.82 g, 0.47 mol, 60% in mineral oil). After effervescence had ceased, benzyl bromide (80.45 g, 0.47 mol) was added dropwise at 0° C. over a 45 min period. The reaction mixture was allowed to warm to RT over a 6 h period. Excess NaH was quenched with MeOH (120 mL) at a temperature below 5° C. The mixture was warmed to RT, diluted with H2O, and the two layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, concentrated, and purified by column chromatography eluting with petroleum ether and EtOAc (PE/EA=40/1 to 30/1) to give the title compound as an oil (45.28 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.41 (m, 2 H), 2.49-2.54 (m, 2 H), 4.20-4.24 (m, 1 H), 4.42 (s, 2 H), 5.62 (s, 2 H), 7.17-7.28 (m, 5 H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][CH:4]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][N:2]([CH3:15])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][CH:4]=1
Reactant: [H][H]
Reactant: CN(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)c1c[nH]c2ncc(N)cc12
Yield: 39.8 %

Procedure:
N,N-Dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-amine (50 mg) was taken up in methanol (3 mL) and EtOAc (3 mL). 10% Pd/C (50 mg) was added, and the mixture was hydrogenated under a balloon of hydrogen for one hour. The mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to a solid. This material was purified by preparative TLC (0.5 mm plate, 10% MeOH/DCM/0.5% NH4OH) to give N3,N3-dimethyl-1H-pyrrolo[2,3-b]pyridine-3,5-diamine (17 mg, 40%). (APCI-pos) M+1=177.2.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33][CH2:34][NH2:35]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:29])[NH:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: COCCCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Product: COCCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Yield: 64 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 3-methoxypropylamine. And then, the product was recrystallized with methanol and isopropyl ether to give a desired compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 41.6 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (10 g) and 1-benzyl-4-hydroxypiperidine (11.5 g), the title compound (7 g) was obtained as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc(O)cc1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.07 h
Yield: 35.2 %

Procedure:
The product of Example 48A (3.21 g, 13.3 mmol) was dissolved in CH2Cl2 (30 mL), cooled to −78° C. and treated with BBr3 (8.31 g, 3.26 mmol). The resulting dark red solution was stirred at 25° C. for 4 min, then cooled to −78° C. Methanol (100 mL) was added slowly. The solution was concentrated in vacuo. Toluene was added to the crude and concentrated again. After adding more toluene, the solution was washed with water and concentrated in vacuo. The residue was dissolved in ether and extracted with NaOH (1.0 g) in water (8 mL). The aqueous layer was removed and stirred 15 minutes, then acidified with concentrated HCl. This mixture was extracted with toluene, dried (Na2SO4), filtered, concentrated in vacuo and the residue crystallized from ether and heptane (2:1) to provide the title compound (1.063 g, m.p. 122-125° C.).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)=[O:52])C(O)=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[CH2:39]([C@H:46]([CH2:50][C:51]([N:53]1[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1)=[O:52])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:20]([OH:30])[CH2:21][C@@H:22]([CH:27]([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:5])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 300 mg (0.56 mmole) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-methylhexanamide [prepared as described in Example 1(a)] and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure. Diethyl ether was added to the residue, and the mixture was concentrated by evaporation under reduced pressure. This operation was repeated three times. After the final residue had been dried under reduced pressure for 8 hours, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran. 170 mg (0.61 mmole) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were then added to the suspension. 0.09 ml (0.59 mmole) of 95% diethyl cyanophosphonate and 0.26 ml (1.86 mmole) of triethylamine were then added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 8 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography on silica gel (using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent), to afford 281 mg (yield 72%) of the title compound as white crystals, melting at 83°-86° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2.ClC1C=CC=C(C(OO)=[O:24])C=1.[OH-].[Na+]>C(O)C>[CH3:1][S:2]([C:3]1[C:4]2[C:5]3[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]=3[CH:13]=[CH:14][CH:15]=2)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c3c(cccc13)C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)c1ccc2c3c(cccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 46.5 %

Procedure:
To an ice water cooled stirred suspension of 1.3 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 2) in 25 ml of ethanol is added portionwise over 12 minutes 1.2 g of 85% m-chloroperbenzoic acid at a rate so the temperature is kept below 7° C. Stirring is continued over 1.25 hours. The reaction mixture is poured over crushed ice and 8 ml of 1N sodium hydroxide with stirring. After 15 minutes of additional stirring, the reaction mixture is filtered. The filtrate is extracted with methylene chloride, dried with magnesium sulfate and evaporated to afford 0.65 g of the desired product as a yellow solid, m.p. 178°-185° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O>C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CCl)COC1CCCCO1
Reaction time: 19 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-2,2-dimethylpropanol (5.0 g) and 2,3-dihydropyran (4.12 g) in ethyl acetate (20 ml) was added camphor sulfonic acid (57 mg), and the mixture was stirred for 19 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with O.1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and distilled under reduced pressure (2 mmHg, 108° C.) to give colorless oil of 2-(3-chloro-2,2-dimethylpropoxy)tetrahydropyran (6.07 g).
Reaction SMILES: CC(OC([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=O)(C)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[NH2:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Solvent: c1ccncc1
Solvent: O
Product: Nc1nc2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-aminobenzothiazol-2-yl tert-butyl carbamate (Intermediate 4, 0.900 g, 3.39 mmol) in pyridine (8 mL), 4-trifluoromethoxybenzoyl chloride (0.535 mL, 3.39 mmol) was added. After stirring for 2 h at 60° C., the solution was poured into water (100 mL). The resulting precipitate was filtered off, washed with water and dried. The so obtained solid was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) was added. After stirring for 3 h at r.t., the volatiles were removed in vacuo and dimethyl-formamide (100 mL) was added to the residue. The solution was neutralised by adding saturated sodium hydrogencarbonate solution. Water (400 mL) was added and the mixture was stirred overnight. The precipitated N-(2-aminobenzothiazol-6-yl)-4-trifluoromethoxy-benzamide was filtered off, washed with water and dried (grey solid, 1.16 g, 3.27 mmol, 84%). LC/ESI-MS: m/z=354 [M+H]+; m/z=352 [M−H]−; Rt=3.20 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH:9]1[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:9]1([CH2:8][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:11][CH2:10]1
Reactant: Ic1cn[nH]c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cnn(CC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Iodo-1H-pyrazole (0.50 g, 2.5 mmol), bromomethyl cyclopropane (0.75 mL, 7.5 mmol), and cesium carbonate (1.20 g, 3.75 mmol) were combined in DMF (10 mL) and stirred at room temperature for overnight. The mixture was subjected to standard aqueous workup, and the crude residue was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: O=C(Cl)CF
Reactant: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2N)c1C
Product: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c1C
Yield: 87.2 %

Procedure:
3.6 g of N-(2-amino-5-nitrobenzoyl)-2,3-dimethylaniline and 1.82 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 3.8 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,3-dimethylaniline are obtained as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:28][O:27][C:24]1[CH:23]=[C:20]([C@H:21]2[S:15][C@H:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[OH:26]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(O)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl-1,2-ethanedithiol (40) (2.46 g, 10.0 mmole), 3,5-dimethoxy-4-hydroxybenzaldehyde (indicated as arylaldehyde E in FIG. 1) (1.32 g, 7.20 mmole) and 1.00 g of pyridinium paratoluene sulfonate are added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer is washed with 10% NaHCO3 and H2O. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to a white solid which is recrystallized from methanol (2.510 g, 85%). The trans isomer (0.683 g) is isolated by recrystallization from methanol. NMR: (CDCl3) 3.45,dd,1H;3.61,dd,1H; 3.91,s,6H;3.92,s,6H;5.07,dd,1H;5.50,d,2H;5.83,s,1H; 6.73,s,2H;6.84,s,2H. M.S.: (CI) 411 (100%). Melting Point: 169°-170° C. C,H,S Analysis: (theoretical, actual) C (55.59,55.58); H (5.40,5.44); S (15.62,15.56).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]=[CH2:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([P:20]([CH3:23])([CH3:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:47]1[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:54].CCN(C(C)C)C(C)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[C:47]=1/[CH:12]=[CH:11]/[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([P:20]([CH3:22])([CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Reactant: Cc1cccc(C)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an oven-dried 50 mL round-bottom flask were added 2-chloro-N-(4-(dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (0.32 g, 0.93 mmol), Pd(OAc)2 (10 mg, 0.05 mmol), tri-o-tolylphosphine (30 mg, 0.1 mmol), 2-iodo-m-xylene (0.39 g, 1.67 mmol). The mixture was flushed with Ar and then dissolved in ˜10 mL anhydrous DMF. DIEA (0.39 g, 2.79 mmol) was then added via syringe. The reaction was stirred at 110° C. overnight. The reaction was diluted with EtOAc and filtered through celite, washed with ample ˜5% MeOH/EtOAc, the combined organic layer was washed with water twice, dried over Na2SO4. Final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C(=O)(O)[O-:13].[Na+]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:11])=[O:13])=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(CC#N)cn1
Agent: [Na+]
Product: COc1ccc(CC(N)=O)cn1
Yield: 52.2 %

Procedure:
The compound 2-(6-methoxypyridin-3-yl)acetonitrile (0.60 g, 4.05 mmol) in poly phosphoric acid (6 g) was stirred at 95° C. for 1 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution and the compound was extracted with DCM (3×20 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude compound was washed with ether (2×5 ml) to afford 350 mg (52.2%) of 2-(6-methoxypyridin-3-yl)acetamide as white color solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCN3CCOCC3)n2)c1F)c1ccoc1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), [2-(4-morpholinyl)ethyl]amine (137 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a white foam (35 mg, 25.6%. 1H NMR (400 MHz, DMSO-d6) ppm 1.62-1.83 (m, 2H), 2.01 (dd, J=12.76, 2.15 Hz, 2H), 2.35-2.47 (m, 7H), 3.23-3.32 (m, 2H), 3.47 (td, J=11.56, 1.89 Hz, 2H), 3.57 (t, J=4.42 Hz, 4H), 3.93 (dt, J=9.35, 2.27 Hz, 2H), 5.81-6.11 (m, 1H), 6.64 (s, 1H), 7.13 (t, J=5.31 Hz, 1H), 7.24 (d, J=5.56 Hz, 2H), 7.44 (dt, J=9.66, 3.76 Hz, 1H), 7.79 (s, 1H), 8.09 (d, J=5.30 Hz, 1H), 8.23 (s, 1H), 10.32 (d, J=1.01 Hz, 1H); MS (ESI): 615.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1.[Mg]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Agent: [Mg]
Solvent: CO
Solvent: ClCCl
Product: Clc1ccccc1-c1c[nH]nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of (17) (1 equiv) in dry MeOH (0.1 M) was added to magnesium powder (10 equiv) under argon at 0° C. and the resulting suspension was stirred at 0° C. for 1 hour, diluted with DCM (3 volumes) and quenched very slowly with 10% HCl (15 ml). The layers were separated and the organic one was washed with 5% aqueous sodium bicarbonate solution and brine, dried (MgSO4), filtered and concentrated in vacuo. An oil was obtained which was purified by flash chromatography (Hex/AcOEt 5:1 and 1:1) to render 4-(2-chlorophenyl)-1H-1,2,3-triazole (18) as a white crystalline solid (42% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH:13]([OH:15])[CH3:14])[CH:10]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH:11]([CH:13]([O:15][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=2)[CH3:14])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a stirred solution of 4-[(3SR,4RS)-1-benzyl-4-((SR)-1-hydroxy-ethyl)-pyrrolidin-3-yl]-benzonitrile (V-A-5) (0.65 g, 2.12 mmol) in DMF (40 mL) at RT was added NaH (55% purity, 0.10 g, 4.1 mmol). After 10 minutes, 6-chloro-nicotinonitrile (0.32 g, 2.33 mmol) was added. The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NH4Cl sat, followed by column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.39 g (45%) of the title compound as a colorless oil. ES-MS m/e: 409.3 (M+H+).