Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Na].[CH2:16]([NH:23][C:24](=[O:47])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36]3[N:37]=[C:38](S(C)(=O)=O)[N:39]=[C:40]([CH3:41])[C:35]=3[CH:34]=[CH:33][C:32]2=[O:46])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:24]([C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:36]3[N:37]=[C:38]([O:1][C:2]4[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=4)[N:39]=[C:40]([CH3:41])[C:35]=3[CH:34]=[CH:33][C:32]2=[O:46])=[CH:29][CH:30]=1)=[O:47])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Oc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)NCc5ccccc5)cc4)c3n2)cc1
Reaction time: 18 h

Procedure:
Ethyl 4-hydroxybenzoate (0.128 mmol) was suspended in THF (1 ml) and NaH (2.9 mg, 0.12 mmol) was added. After formation of the subsequent sodium salt, suspended in THF, the resin (A3) was added and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2>C(OCC)C>[CH2:1]([C:11]1([OH:15])[C:12]2[C:8](=[CH:7][C:6]([F:5])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CCOCC
Product: CCC1(O)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
292 ml (876 mmol) of a 3N solution of ethylmagnesium bromide in diethyl ether were added to 5.00 g (33.3 mmol) of 5-fluoroindan-1-one in 150 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 5.70 g (94% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[NH:18]1[C:26]2[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[CH:20]=[CH:19]1.[OH-].[Na+].C(OCC)(=O)C>CS(C)=O.ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:18]2[C:26]3[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=3[CH:20]=[CH:19]2)[CH2:5][CH2:6]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCn2ccc3c2CCCC3=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 1-(2-Chloroethyl)-4-(2-methoxyphenyl)piperazine (7.30 g) was dissolved in DMSO (30 mL), then slowly added to 1,5,6,7-tetrahyro-indol-4-one (30.1 mmol) which was pretreated with sodium hydroxide (31.6 mmol) in DMSO (15 mL) for 0.5 h with slight heat. The reaction was left under heat and was monitored by TLC (ethyl acetate: dichloromethane, 1:1). After completion (8 h), the reaction mixture was poured in ice water (300 mL) and extracted with dichloromethane twice, dried with sodium sulfate and solvent removed under vacuum. Flash chromatography (ethyl acetate: dichloromethane, 1:4) yielded an oil, NEO-377 (7.25 g).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl[CH2:11][C:12]1[N:16]=[CH:15][O:14][N:13]=1>C(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:11][C:12]1[N:16]=[CH:15][O:14][N:13]=1
Reactant: Nc1ccccc1S
Reactant: ClCc1ncon1
Agent: [Na]
Solvent: CCO
Product: Nc1ccccc1SCc1ncon1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium (1.27 g; 0.055 mol) was dissolved in absolute ethanol (50 ml) and to this was added 2-aminothiophenol (7.38 g; 0.059 mol). To the resulting solution was added 3-chloromethyl-1,2,4-oxadiazole (6.59 g; 0.055 mol) dropwise over 10 minutes. The resulting mixture was then stirred at ambient temperature for 30 minutes, sodium chloride removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole which was re-crystallised from isopropanol; m.p. 57°.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]([C:28]2[N:29]=[C:30]([NH:33]C(=O)CCl)[S:31][CH:32]=2)[C:16]([NH:18][CH:19]2[CH2:22][N:21]([S:23]([O-:26])(=[O:25])=[O:24])[C:20]2=[O:27])=[O:17])=[O:13])[N:10]=1)=O.[Na+:41].CNC(=S)[S-].[Na+]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]([C:28]2[N:29]=[C:30]([NH2:33])[S:31][CH:32]=2)[C:16]([NH:18][CH:19]2[CH2:22][N:21]([S:23]([O-:26])(=[O:24])=[O:25])[C:20]2=[O:27])=[O:17])=[O:13])[N:10]=1.[Na+:41]
Reactant: CON=C(C(=O)NC(C(=O)NC1CN(S(=O)(=O)[O-])C1=O)c1csc(NC(=O)CCl)n1)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC(C(=O)NC1CN(S(=O)(=O)[O-])C1=O)c1csc(N)n1)c1csc(N)n1
Yield: 63.3 %

Procedure:
In 3 ml of water is dissolved 0.204 g of the above sodium 3-[2-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-(2-chloroacetamido-4-thiazolyl)acetamido]-2-oxoazetidine-1-sulfonate (syn-isomer) and while the solution is stirred under ice-cooling, 0.085 g of sodium N-methyldithiocarbamate is added. The mixture is stirred for an hour, after which the insoluble matter is filtered off. The filtrate is purified by Amberlite XAD-II chromatography to provide 0.1 g of sodium 3-[2-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-(2-amino-4-thiazolyl)acetamido]-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:52](=[O:53])[CH2:51][CH2:50][S:49][CH2:48][CH:47]([O:46][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:14][CH:13]=1)(=[O:10])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NS(=O)(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-aminobenzenesulfonylglutamic acid di-t-butyl ester (189 mg) in pyridine (2.3 ml), phosphorus trichloride (0.023 ml) was added, followed by stirring at room temperature for 2 hours. To the mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (213 mg, yield 89%) as a wax-like substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:15]([Cl:21])=[O:17])[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)Cl)c2ccccc2c1C#N

Procedure:
To a stirred solution of 3,4-dicyano-1-naphthoic acid (121 mg, 0.542 mmol) in dry DCM (5 mL) was added oxalyl chloride (80.0 mg, 0.63 mmol) and DMF (10 μL). After 3 h at room temperature DCM was removed in vacuo to afford 3,4-dicyano-1-naphthoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([O:21]C)=O)[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.B(OCCCC)(OCCCC)OCCCC.CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[O:21])[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1C
Solvent: CO
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3cc(Cl)ccc3n2C)S1(=O)=O
Yield: 70 %

Procedure:
3.0 gm (8.4 millimols) of methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide, 0.9 gm (9 millimols) of 2-amino-thiazole and 50 mgm of tri-n-butyl borate were refluxed in 300 ml of dry xylene for 6 hours. The methanol released by the reaction was separated by means of a 4-A-molecular sieve in a Soxhlet-attachment. 3.1 gm of crystals were separated from the cooled reaction mixture by filtration and subsequently boiled in a mixture of 100 ml of acetonitrile and 1 ml of glacial acetic acid. After filtration and drying, 2.5 gm (68% of theory) of 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide were obtained; M.p.: 282° C. (decomposition).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(Cl)=S)C1C=CC=CC=1>ClCCCl.CN(C)C1C=CN=CC=1>[C:1]([O:9][C@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: S=C(Cl)Oc1ccccc1
Solvent: ClCCCl
Product: O=C(OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)C[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of 1-(3,5-di-O-benzoyl-β-L-arabinofuranosyl)uracil 12 (5.2 g, 11.4 mmoL) in anhydrous 1,2-dichloroethane (120 mL) were added phenoxythiocarbonyl chloride (4.7 mL, 34.3 mL) and 4-(dimethylamino)pyridine (DMAP, 12.5 g, 102.6 mmoL). The resulting solution was stirred at room temperature under argon atmosphere for 1 h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and the organic solution was successively washed with an ice-cold 0.2 N hydrochloric acid solution (3×200 mL) and water (2×200 mL), dried over Na2SO4 then evaporated under reduced pressure. The crude material was co-evaporated several times with anhydrous dioxane and dissolved in this solvent (110 mL). To the resulting solution were added under argon tris-(trimethylsilyl)silane hydride (4.2 mL, 13.7 mmol) and α,α′-azoisobutyronitrile (AIBN, 0.6 g, 3.76 mmol). The reaction mixture was heated and stirred at 100° C. for 1 h under argon, then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%)] to give 13 (2.78 g, 56%) which was crystallized from EtOH: mp=223-225° C.; 1H-NMR (DMSO-d6): δ 11.4 (br s, 1H, NH), 8.0-7.5 (m, 11H, 2 C6H5CO, H-6), 6.28 (t, 1H, H-1′, J=7 Hz), 5.5 (m, 2H, H-1′ and H-5), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 2H, H-2′ and H-2″); MS: FAB>0 (matrix GT) m/z 437 (M+H)+, 3325 (S)+; FAB<0 (matrix GT) m/z 435 (M−H)−, 111 (B)−; Anal. Calcd for C23H20N2O7: C, 63.30; H, 4.62; N, 6.42. Found: C, 62.98; H, 4.79; N, 6.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-chloro-pyridin-4-yloxy)-phenylamine (Example 105) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a beige solid: ES-MS: 407.9 [M+H]+; single peak at tR=9.99 min (System 2); Rf=0.30 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][CH:50]([CH3:59])[CH:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[OH:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:52][CH:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]([CH3:59])[CH3:49])=[CH:18][CH:17]=1
Reactant: CC(C)C(O)c1ccccc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(c4ccccc4)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 31.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (137 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-methyl-1-phenyl-1-propanol (56 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (38 mg, yield 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[CH:4]([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([Pb+3])=[C:31]([CH2:36][CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:6]2[C:5](=[O:9])[CH:4]([CH3:10])[O:3][C:2]([CH3:11])([CH3:1])[C:7]2=[O:8])=[C:31]([CH2:36][CH3:37])[CH:30]=1
Reactant: CC1OC(C)(C)C(=O)CC1=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Temperature: 80 °C
Yield: 23 %

Procedure:
2,2,6-Trimethylpyran-3,5-dione (1 g, 6.4 mmol) and 4-dimethylaminopyridine (3.9 g, 32 mmol) are added to a mixture of chloroform (20 ml) and toluene (5 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (4.3 g, 7.57 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with chloroform (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione as a white solid (0.5 g).
Reaction SMILES: [C:1](Cl)(=[O:3])N.[CH2:5]([NH:12][C:13](=[N:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:14][CH2:15][CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>C1C=CC=CC=1>[CH2:18]([N:17]([C:1](=[O:3])[N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:13](=[N:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[S:14][CH2:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NC(=O)Cl
Reactant: CCNCC
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: c1ccccc1
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)N(CC)CC
Temperature: 15 °C

Procedure:
100 ml of dry benzene and 5.44 g of 1,3-diheptyl-2-ethyl isothiourea carbamyl chloride were placed in a 200 ml flask equipped with a thermometer and dropping funnel. A solution of 12 ml dry benzene and 2.19 g diethyl amine was added dropwise over 10-12 minutes. An exotherm raised the temperature from 21° to 30° C. The mixture was then heated to 45°-50° C. for 3 hours. The reaction mixture was then cooled to 15° C. and washed twice by 50 ml portions of cold water. The benzene phase was dried by MgSO4, filtered and the solvent removed under reduced pressure. 5.75 g of a liquid (96 weight percent of theory) having a nD30 of 1.4568 was recovered. The structure was confirmed as the title compound by mass spectra analyses. Compound No. 644 in Table I.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:23]=2[S:24][C:25]=1[CH3:26])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:22]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[S:10][C:3]=34)=[CH:27][C:23]=2[S:24][C:25]=1[CH3:26])=[O:20]
Reactant: Clc1ccnc2cc(CN3CCCC3)sc12
Reactant: CNC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4cc(CN5CCCC5)sc34)ccc12

Procedure:
This material was prepared from 7-Chloro-2-(pyrrolidin-1-ylmethyl)thieno[3,2-b]pyridine 115a, 6-hydroxy-2-methyl-benzo[b]thiophene-3-carboxylic acid methylamide 1d and cesium carbonate in a similar manner as described in example 1. 1H-NMR (DMSO-d6, 400 MHz) 68.44 (1H, d, J=5.3 Hz), 8.27 (1H, q, J=4.6 Hz), 7.91 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.6 Hz), 7.43 (1H, s), 7.28 (1H, dd, J=2.3, 8.6 Hz), 6.60 (1H, d, J=5.6 Hz), 3.93 (2H, s), 2.82 (3H, d, J=4.8 Hz), 2.60 (3H, s), 2.54 (4H, bs), 1.72 (4H, s); MS m/z 438 (M+H)+;
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37][CH2:36]4)=[C:28]4[C:32]=3[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]4)[C:20]([C:44]([F:47])([F:46])[F:45])=[CH:19][N:18]=2)=[C:12]([O:48][CH3:49])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH3:50][N:51](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].C[NH3+].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:49][O:48][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C@H:35]3[CH2:36][CH2:37][C@@H:38]([C:41](=[O:42])[NH:51][CH3:50])[CH2:39][CH2:40]3)=[C:28]3[C:32]=2[C:31](=[O:33])[N:30]([CH3:34])[CH2:29]3)[C:20]([C:44]([F:47])([F:46])[F:45])=[CH:19][N:18]=1)[CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)NC)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
cis-4-(7-{[2-({4-[(Diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylic acid (10.0 mg, 0.0142 mmol), TBTU (9.1 mg, 0.0283 mmol) and DMF (0.8 mL) were mixed and the mixture was stirred at room temperature for 30 minutes. Methylammonium chloride (9.6 mg, 0.142 mmol) and DIPEA (24.7 μL, 0.142 mmol) were added and the mixture was stirred at room temperature for 2 hours. The crude was purified by MDP to obtain the title compound (4.4 mg, 43% yield). 1H NMR (400 MHz, methanol-d4) δ=1.29 (t, J=7.1 Hz, 6H), 1.67-1.81 (m, 4H), 1.87-2.01 (m, 2H), 2.15 (d, J=12.4 Hz, 2 H), 2.60 (br. s., 1H), 2.71 (t, J=11.2 Hz, 1H), 2.79 (s, 3H), 3.18 (s, 3H), 3.37 (d, J=21.7 Hz, 2H), 3.90 (s, 3H), 4.10 (quin, J=7.3 Hz, 4H), 4.53 (s, 2H), 6.99 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.34 (br. s., 1H), 7.67 (d, J=8.1 Hz, 1H), 8.33 (br. s., 2H). MS (ES+): m/z 719.36 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[O:10][S:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)(=[O:21])=[O:20]
Reactant: Cc1c(Cl)ccc(O)c1Cl
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(OS(=O)(=O)c2nc[nH]n2)c1Cl

Procedure:
2.33 g of 2.4-dichloro-3-methylphenol was dissolved in 15 ml of tetrahydrofuran, and 1.84 ml of triethylamine was added while stirring the solution. Then, 2.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, the solution was stirred at room temperature for 14 hours. Tetrahydrofuran was removed by distillation at reduced pressure, 2N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was washed with brine, and dried with magnesium sulfate. Then, the solvent was removed by distillation, so that coarse crystals were obtained. The coarse crystals were recrystallized from n-hexane/ethyl acetate, so that 2.25 g of the titled compound was obtained.