Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[O:9])=[N:20][C:16]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncnc(N4CCCCC4)c3C)nc2c1

Procedure:
A solution of m-chloroperbenzoic acid (2.16 g) in dichloromethane (40 ml) was added to a stirred solution of 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole (4.0 g) in dichloromethane (110 ml) cooled to between -40° and -50°. After a further hour at -40°, ammonia was passed through the reaction mixture and the precipitated solid filtered off. The filtrate was stripped, and the residual glass triturated with acetonitrile to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole, 2.66 g, m.p. 87°-89°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]#[N:13])[CH:8]=[C:7]2[S:14]([CH3:17])(=[O:16])=[O:15].[CH2:18](N)[CH2:19][NH2:20]>C(=S)=S>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[NH:20][CH2:19][CH2:18][N:13]=1)[CH:8]=[C:7]2[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: NCCN
Reactant: CS(=O)(=O)c1cn(CC#N)c2c(Cl)cccc12
Solvent: S=C=S
Product: CS(=O)(=O)c1cn(CC2=NCCN2)c2c(Cl)cccc12
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
(7-chloro-3-methanesulfonyl-indol-1-yl)-acetonitrile (2.1 g) from Step 7 was dissolved in ethylene diamine (10 ml) and 2 drops of carbon disulfide were added. The flask was blanketed with nitrogen and then placed in an oil bath previously heated to 140° C. The mixture was stirred and after 30 minutes checked by mass spec which revealed the complete absence of starting material and the appearance of the desired product (positive ion spectrum) as well as an undetermined amount of unalkylated impurity from the previous reaction (negative ion spectrum). After 45 minutes, the reaction was cooled to room temperature and then placed in an ice bath. The product crystallized. Ethyl acetate (10 ml) was added and the precipitate was broken up, filtered, and then washed with a bit of ethyl acetate followed by ether. Air drying gave 1.22 g of a colorless crystalline solid, 7-chloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indole which after vacuum drying overnight at 60° C. weighed 1.21 g. The material was analytically pure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][NH:19][C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>CC(C)CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NCCCl)c1cccnc1
Solvent: CC(=O)CC(C)C
Product: O=C(NCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1cccnc1
Yield: 16.5 %

Procedure:
To a stirred solution of 11.2 parts of (4-fluorophenyl)(4-piperidinyl)methanone in 80 parts of 4-methyl-2-pentanone were added 5 parts of N-(2-chloroethyl)-3-pyridinecarboxamide and the whole was stirred and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.6 parts (16.5%) of N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3-pyridinecarboxamide; mp. 118.3° C. (intermediate 114).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH:21](N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=N[C:37]2[N:40]([OH:43])N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([N:40]([O:43][CH3:21])[CH3:37])=[O:12])=[CH:6][CH:7]=1
Reactant: On1nnc2cccnc21
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 945.2 %

Procedure:
3-(4-bromophenyl)-2-(4-methoxyphenyl)propanoic acid (3.0 g, 8.95 mmol), Weinreb amine (1.05 g, 10.7 mmol) were dissolved in DMF (90 ml) and diisopropylethylamine (1.88 ml, 10.7 mmol) was added in one portion. EDC (2.06 g, 10.7 mmol) and HOAt (0.122 g, 0.895 mmol) were added to the resulting solution portionwise. The resulting solution was allowed to stir at 25° C. for 1 hour. After one hour the reaction was diluted with EtOAc, washed with 10% KHSO4, saturated NaHCO3, and LiCl (×3). The organic layer was dried over sodium sulfate and concentrated in vacuo, which afforded 3.2 g of 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide as a colorless oil. 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide (1.0 g, 2.64 mmol) was dissolved in anhydrous THF (26.4 ml) and the resulting solution was cooled to 0° C. MeMgBr (1.32 ml, 3.97 mmol) was added dropwise to the cooled solution, and the resulting solution was allowed to stir for 30 min. at 0° C. The solution was then warmed to 25° C. for one hour, at which point the solution was filtered over a pad of celite and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (0-40% EtOAc in hexanes gradient to afford 627 mg of 4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].P([O-])([O-])([O-])=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of 1.5 g of (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one in 100 ml of dichloromethane, at room temperature and under inert atmosphere, 0.069 g (0.56 moles) of 4-dimethylamino pyridine and 0.5 ml of pyridine are added. To this mixture 0.907 g (6 mmoles) of tert-butyldimethylchlorosilane dissolved in 10 ml of anhydrous dichloromethane are slowly added. The mixture is let under stirring for about 24 hours, then a phosphate buffer at pH 7.5 is added. The organic phase is extracted with dichloromethane and the dichloromethane phase is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum. Thus, essentially pure (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldimethylsilyl-azetidin-2-one (III, R=TBDMS) is obtained in quantitative yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[N:13]([CH:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]=[S:15]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:14](=[S:15])[NH:13][CH:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCOC(=O)CC(C)N=C=S
Agent: Cl
Product: CCOC(=O)CC(C)NC(=S)NS(=O)(=O)c1sc(Cl)cc1N

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and ethyl 3-isothiocyanatobutyrate by a procedure analogous to the procedure described in example 3-a (yield 93%); 1H-NMR (DMSO-d6): δ1.18 (d, 3H, CH3), 1.20 (t, 3H, CH3), 2.61 (m, 2H, CH2), 4.08 (q, 2H, CH2), 4.58 (m, 1H, CH), 6.46 (br s, 2H, NH2), 6.65 (s, 1H, H-4), 8.34 (br d, 1H, NH), 11.35 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH3:2].[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C(C)=CC=CC=1.[Cu](I)I>[CH3:18][C:19]1[CH:20]=[C:21]([N:25]([C:7]2[CH:6]=[CH:5][C:4]3[N:3]([CH2:1][CH3:2])[C:15]4[C:10]([C:9]=3[CH:8]=2)=[CH:11][C:12]([N:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([CH3:46])[CH:41]=2)=[CH:13][CH:14]=4)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccccc1
Reactant: CCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: Cc1cccc(Nc2ccccc2)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCn1c2ccc(N(c3ccccc3)c3cccc(C)c3)cc2c2cc(N(c3ccccc3)c3cccc(C)c3)ccc21
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
In an argon atmosphere, 16.59 g (30 mmol) of N-ethyl-3,6-dibromocarbazole and 12.09 g (66 mmol) of N-(3-methylphenyl)-N-phenylamine are dissolved in 1.00 ml of dehydrated xylene. Then, 5.7 g (30 mmol) of copper iodide and 22.8 g (200 mmol) of trans-cyclohexanediamine are added to the xylene solution, and are stirred at 160° C. for 30 minutes. After the stirring, 27.6 g (130 mmol) of potassium phosphate is added, and the mixture is further stirred for 9 days. After the stirring and cooling to a room temperature, 300 ml of toluene is added, and a precipitate is filtered out. The obtained filtrate is condensed, diethyl ether is added to the filtrate, and a precipitate is filtered out. Then, when methanol is added to the obtained filtrate, a tarry object is precipitated on a wall surface of a beaker. The filtrate with the tarry object is left at rest overnight, and the liquid phase is removed by decantation to obtain the tarry object. This obtained tarry object is purified by silica gel column purification using hexane:chloroform (1:2) to obtain 3,6-bis[N-(3-methylphenyl)-N-phenylamino]-9-ethylcarbazole (the above structural formula (56); hereinafter, referred to as EtCzmP2) that is light brownish green powder. The obtained EtCzmP2 is purified by sublimation at a higher temperature of 300° C. and a lower temperature of 200° C. The yield after the sublimation purification is approximately 10%.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:17][OH:18])=[C:11]([C:13](O)([CH3:15])[CH3:14])[CH:12]=1>O1CCOCC1.O>[Br:6][C:7]1[CH:12]=[C:11]2[C:10]([CH2:17][O:18][C:13]2([CH3:14])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OCc2ccc(Br)cc21
Temperature: 60 °C
Yield: 86.3 %

Procedure:
H2SO4 (0.4 mL conc, 1.6 mL H2O) was added to a solution of Intermediate 388.1 (0.25 g, 1.02 mmol) in dioxane (2 mL). The mixture was stirred at 60° C., diluted with H2O (10 mL), extracted with hexanes (2×25 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated to yield 200 mg of Intermediate 388.2 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 6H) 5.01 (s, 2H) 6.98 (m, 1H) 7.32 (m, 1H) 7.37 (m, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH:12]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[C:25](=[O:26])[N:24]=[CH:23][NH:22][C:21]=3[N:27]=2)[CH2:15][CH2:14][O:13]1.Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[Cl:37]>C1COCC1>[Cl:37][C:31]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:22]1[C:21]2[N:27]=[C:18]([N:16]3[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]3)[S:19][C:20]=2[C:25](=[O:26])[N:24]=[CH:23]1
Reactant: CC1CN(c2nc3[nH]cnc(=O)c3s2)CCO1
Reactant: Clc1cccc(CBr)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(c2nc3c(s2)c(=O)ncn3Cc2cccc(Cl)c2Cl)CCO1
Yield: 42.5 %

Procedure:
LiHMDS (0.9 N, 2.7 mL, 2.4 mmol) was added to a solution of 2-(2-methylmorpholino)thiazolo[4,5-d]pyrimidin-7(4H)-one (300 mg, 1.2 mmol) in THF (6.0 mL) at 0° C. The reaction mixture was stirred for an hour. 1-(bromomethyl)-2,3-dichlorobenzene (285 mg, 1.2 mmol) was added to the mixture and the resultant mixture was stirred for 18 hours. The reaction was quenched by water and extracted with dichloromethane. The organic layer was dried, concentrated and purified through silica gel chromatography to give the desired product as a solid (210 mg, 43%). 1H NMR (300 MHz, d6-DMSO) δ 8.48 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.35 (m, 1H), 7.18 (d, J=7.8 Hz, 1H), 5.47 (s, 2H), 3.89 (m, 1H), 3.82˜3.75 (m, 2H), 3.56˜3.52 (m, 2H), 3.26˜3.16 (m, 1H), 2.91 (m, 1H), 1.14 (d, J=6.0 Hz, 3H); LC-MS: 411 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].O.Cl>CN(C=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[N:16][O:17][C:18]=3[CH3:19])[C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3noc(C)c23)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(O)cc3)c12
Temperature: 100 °C
Yield: 53.7 %

Procedure:
To 1.05 g of 4-(4-methoxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one (4.08 mmol) in 15 mL dry DMF was added 1.03 g of sodium ethanethiolate in 15 mL dry DMF at room temperature. The reaction was then heated at 100° C. for 2.5 h. Added water and 1M HCl until acidic. Extracted the product with diethyl ether and dried the extracts with Na2SO4, filtered, and concentrated in vacuo. The product was purified via silica gel chromatography eluting with 95:5 dichloromethane:methanol to give 533 mg of 4-(4-hydroxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one; Mp 268-276° C.; MS m/z 216 (M-N2+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][OH:22]>CCO.C(#N)C>[OH:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Solvent: CCO
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCCO)cc2)oc2ncccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a 100 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.0 g, 4.18 mmol) in EtOH (10 mL) and acetonitrile (50 mL). 2-Chloroethanol (2.05 g, 25.0 mmol) was added slowly and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by column chromatography, using 2% MeOH in dichloromethane to afford 2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one (380 mg, 32% yield). MS (ES) m/z: 284.94 (M+1), 283.95 (M); Mp. 157-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])=O.[NH4+:14]>CO>[NH2:14][C:9]1[CH2:8][CH2:7][CH2:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C1CCCC1=O
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C1=C(N)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 10.00 g (70.35 mmol) of methyl cyclopentanone-2-carboxylate in 100 ml of methanol, 22.18 g (351.74 mmol) of ammonium formate was added, and the resulting mixture was heated under reflux for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue, 50 ml of ethyl acetate and 30 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed twice with each 30 ml of water and once with 30 ml of a brine successively and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from methanol to give the objective methyl 2-amino-1-cyclopentenecarboxylate (7.34 g, white crystals). The yield was 73.9%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][N:34](C)[CH2:35][CH2:36][CH2:37]N=C=NCC.CNCCC>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([C:8](=[O:9])[N:34]([CH3:33])[CH2:35][CH2:36][CH3:37])[CH:11]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N(C)CCC)c1
Yield: 90.1 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol), N-methylpropylamine (51 μL, 0.5 mmol) in dichloromethane (2.5 mL) at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 90%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.C(OCC)C>COCCOCCOC>[C:10]1([NH:9][C:2]2[N:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Oc1cc(Cl)ncn1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: Oc1cc(Nc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
6-Chloropyrimidin-4-ol (500 mg, 3.85 mmol), aniline (420 μL, 4.62 mmol) and N,N-diisopropylethylamine (1 mL) in diethylene glycol dimethyl ether (5 mL) was heated to 120° C. and stirred for 8 h. The mixture was cooled to room temperature then diluted with actone:diethyl ether solution (1:1, 15 ml) to give a precipitate. The solid collected by filtration and washed with acetone then dried to afford 6-(phenylamino)pyrimidin-4-ol (255 mg, 35.5%). MS (EI) for C10H9N3O: 188.2 (MH+).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N1CCC(=O)CC1
Temperature: 78 °C
Yield: 60.9 %

Procedure:
To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g, 0.148 mol) and sodium bicarbonate (1.245 g, 0.014 mol) in water (60 ml). The reaction mixture was heated at 78° C. for 6 hours and then allowed to cool to ambient temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine, dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14 g) (LC/MS: Rt 0.39, [M+H]+ 156).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].CS(C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:6]2[C:5]3[S:9][CH:10]=[CH:11][C:4]=3[S:3](=[O:13])(=[O:12])[N:2]([CH3:1])[C:7]=2[OH:8])=[O:27])=[CH:21][CH:20]=1
Reactant: CN1C(=O)Cc2sccc2S1(=O)=O
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 G. of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide are dissolved in 31 ml. of absolute dimethylsulfoxide under an atmosphere of nitrogen. 1.44 G. of freshly distilled triethylamine and 2.83 g. of 4-bromophenyl isocyanate are added to the solution and the mixture is then stirred for 24 hours at room temperature. This mixture is then poured into 225 ml. of 3-N hydrochloric acid and the precipitate which separates out is filtered on a sinter filter, washed three times with 20 ml. of distilled water each time and dried as much as possible. The precipitate is dissolved in 250 ml. of methylene chloride, dried over sodium sulfate, stirred with activated charcoal and filtered. The organic phase is shaken out four times with 250 ml. of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride. The combined aqueous phases are rendered strongly acid with concentrated hydrochloric acid. The product which separates out is extracted three times with 250 ml. of methylene chloride each time. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and the solvent is removed by distillation. The crystalline residue is dissolved in 50 ml. of chloroform. While boiling, activated charcoal is added and the mixture is filtered hot. The product is made to crystallize by scratching. The crystals are removed by filtration, digested with a little cold chloroform, and 4'-bromo-3-hydroxy-2-methyl-2N-thieno[[2,3-e] 1,2-thiazine-4-carboxanilide 1,1-dioxide, melting point 178° C. to 179° C. (decomposition), is obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[C:17]([F:20])([F:19])[F:18].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][C:11]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Triethylamine (6.24 ml, 44.8 mmol) was added to a solution of 4-methoxy-3-(trifluoromethyl)aniline (4.29 g, 22.4 mmol) in dichloromethane (45.0 ml), and the resulting mixture was ice-cooled, followed by adding dropwise thereto pivaloyl chloride (2.84 g, 23.5 mmol) at 0 to 5° C. The resulting mixture was warmed up to room temperature and stirred for 1 hour while maintaining the temperature. The mixture was partitioned by the use of a 5%-aqueous sodium hydrogencarbonate solution and ethyl acetate, and the organic layer was washed with a 5% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain N-[4-methoxy-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (6.16 g, 100%).