Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH:40]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,3-dimethylbutyraldehyde instead of acetone and was obtained as a light brown oil. MS m/e: 608.2 [M]+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[ClH:8].[CH2:9](O)[CH3:10]>>[ClH:8].[NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:9][CH3:10])=[O:4]
Reactant: CCO
Reactant: CC(C)(N)C(=O)O
Agent: Cl
Product: CCOC(=O)C(C)(C)N

Procedure:
A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0° C. was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid. Sodium carbonate (100 g) was slowly added to a suspension of the solid in water followed by 40% aqueous formaldehyde solution (150 g) and the suspension was stirred for 3 hours. The mixture was extracted with ether, the organic solution was washed with water, dried (magnesium sulphate) and solvent evaporated under reduced pressure to give ethyl 2-(N-methyleneamino)-2-methylpropanoate (137.8 g) in equilibrium with its trimer 1,3,5-tri(1-ethoxycarbonyl-1-methylethyl)hexahydrotriazine as a colourless oil, IR (liquid film) 2980(s), 1725(vs), 1250(s), 1140(vs).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: Brc1cncnc1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1cncnc1)c1ccccc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 L 4-neck flask under a nitrogen atmosphere was charged with 4.4 g. of 60% sodium hydride (1.1 equiv., 0.11 moles), and washed with hexanes, in 75 ml. DMF. Then over 30 minutes, 27.3 g. of 4-(4-chlorophenyl)-2-(2-fluorophenyl) butanenitrile (1.0 equiv., 0.10 moles) in 110 ml. DMF was added dropwise to the base causing an exotherm to 30° C. After the addition was complete, the reaction mixture was stirred for 30 minutes. Over 5 minutes 17.5 g. of 5-bromopyrimidine (1.1 equiv., 0.11 moles) in 75 mi. DMF was added to the reaction mixture which was heated at 50° C. and monitored by GLC analysis. The reaction was quenched after 2 hours by the addition of 350 ml. water and extracted with 600 ml. ethyl acetate. The organic phase was washed with three 300 ml. portions of water, the organic phase dried over anhydrous magnesium sulfate, and then concentrated in vacuo at 50° C. to give 34.2 grams oil which solidified. The solid was with triturated with 75 ml. isopropanol, filtered, and dried to give 16.5 g. white solid (47.0% yield), m.p.=86° C.-88° C.
Reaction SMILES: C(#N)C.[CH:4]([NH2:7])([CH3:6])[CH3:5].Cl[C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1>C(OCC)C>[CH3:5][CH:4]([NH:7][C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[C:12]([C:14]([F:16])([F:15])[F:17])[N:13]=1)[CH3:6]
Reactant: CC(C)N
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Yield: 62 %

Procedure:
A reaction vessel was charged with 25 ml of acetonitrile, 2.94 g (49.8 mmol) of iso-propylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506). The reaction mixture was heated at reflux for 16 hours. The mixture was then cooled to ambient temperature, diluted with ethyl ether, washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 5.32 g of a gold oil. This oil was subjected - to Kugelrohr distillation (145°-155° C. @ 0.5 mm Hg) to yield 4.97 of a gold oil which was then triturated in hexane to yield 3.99 g of a yellow solid product (m.p.=49°-53° C.) identified in Table I.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[C:6]3[NH:7][C:8](=[O:15])[C:9](=[O:14])[NH:10][C:11]=3[CH:12]=[CH:13][C:4]=2[CH2:3]1.[N+:18]([O-])([O-:20])=[O:19].[K+].[OH-].[NH4+].[S:25](=[O:29])(=O)([OH:27])[OH:26]>>[CH3:1][S:25]([OH:27])(=[O:29])=[O:26].[CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[C:6]3[NH:7][C:8](=[O:15])[C:9](=[O:14])[NH:10][C:11]=3[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:4]=2[CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)(O)O
Reactant: CN1CCc2c(ccc3[nH]c(=O)c(=O)[nH]c23)C1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Product: CN1CCc2c(c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)C1
Product: CS(=O)(=O)O
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of the product from Example 22 (1.07 g,4.7 mmol) was dissolved in 20 ml sulfuric acid. Potassium nitrate (0.51 g, 5.0 mmol) was added in one portion, and the solution stirred for 1 hour. The solution was poured onto ice and made basic with ammonium hydroxide. The yellow solid which formed was filtered and washed with water and ether. The solid was purified by crystallization from water. The solid was suspended in water/DMF and 0.5 g methane sulphonic acid was added. The solution was concentrated, and the solid suspended in acetone, filtered and dried under vacuum (100° C.) to give the title compound (0.60 g, 35% yield), mp=292-294° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].Cl.[CH3:13][NH:14][O:15][CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1)=[O:11]
Reactant: CNOC
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3-nitro-1H-pyrazole-5-carboxylic acid (15.7 g, 1.0 eq., 100 mmol), N,O-dimethylhydroxylamine hydrochloride (19.5 g, 2.0 eq., 200 mmol), HATU (76.0 g, 2.0 eq., 200 mmol), triethylamine (40.4 g, 4.0 eq., 400 mmol), and dichloromethane (300 mL). The reaction mixture was stirred at room temperature for overnight. The solvent was removed under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 287a (16.0 g, 80%) as white solid. MS-ESI: [M+H]+ 201.1
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[NH3:25]>CO>[CH3:24][N:6]1[C:5]([C:3]([NH2:25])=[O:2])=[CH:9][C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7]1
Reactant: N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(N)=O)n(C)n1
Yield: 20 %

Procedure:
As described for example 42e, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (170 mg, 0.52 mmol) was converted, using ammonia in methanol instead of ethanolamine, to the title compound (32 mg, 20%) which was obtained as a white solid. MS: m/e=313.1 [M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH4+:10].[OH-]>O>[NH2:10][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: [NH4+]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
A stirred suspension of cyanuric chloride (3.7 g, 30 mM) in water (25 mL) was treated with NH4OH (2.42 mL of a 28% solution diluted to 7.5 mL) at 0° C. Stirring was continued for 1 hr at 0° C. and 0.5 hr at 10° C. The product was filtered and rinsed with water until the filtrates were neutral. Drying (60° C., 0.2 mm) provided 2.84 g, (86%), mp=234°-235° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-2].[Ca+2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>COCCOCCOC>[CH:21]1([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13][C:12]2=3)[CH2:23][CH2:22]1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [Ca+2]
Agent: [O-2]
Solvent: COCCOCCOC
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 46.7 kg of calcium oxide and 47.5 kg of cyclopropylamine (molar ratio: 1:2:2) are heated to 135° to 145° C. in 235 l of diglyme (diethylene glycol dimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and about 188 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. Over a period of 20 to 40 minutes, the resultant diluted solution is added to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470.0 l of water. The reaction mixture is cooled to a temperature of about 25° C. and 235.0 l of cyclohexane and 57.1 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is washed with 235.0 l of methyl tert.-butylether, followed by 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 90.6 kg (81.7% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Cc1ccc(OCCBr)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(OCCN2CCC(CCN(C)C)CC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 4-methylphenyl ether (6.6 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was poured into ice/water (500 ml), basified with 2M sodium hydroxide solution and extracted with dichloromethane. The combined organic extracts were washed with water and then extracted with 2M hydrochloric acid. The combined acidic layers were basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give an oil. The oil was distilled at 120° C. at 0.05 mbar and the distillate was dissolved in ether, acidified with ethereal hydrogen chloride solution and filtered. The solid obtained was washed with ether and recrystallised from absolute ethanol to give 4-(2-dimethylaminoethyl)-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride m.p. 281°-283° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[S:20]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[CH:22]=[CH:21]1>>[S:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:24][C:23]=2[CH:22]=[CH:21]1
Reactant: c1cc2c(s1)CCNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4sccc4C3)n2)c1

Procedure:
B43 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine; yield: 88.6 mg (22%), white amorphous solid. MS (ES) C17H18N6O2S2 requires: 402. found: 403 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:24]([C:26]1[S:27][C:28]([O:31][CH2:32][CH3:33])=[N:29][N:30]=1)[CH3:25]>O.CN(C)C=O>[CH2:32]([O:31][C:28]1[S:27][C:26]([CH:24]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:9][CH:10]=2)[CH3:25])=[N:30][N:29]=1)[CH3:33]
Reactant: Oc1ccc(Oc2ccccn2)cc1
Reactant: CCOc1nnc(C(C)Br)s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccccn3)cc2)s1
Yield: 61.1 %

Procedure:
To a mixture of 4-(2-pyridyloxy)phenol (0.75 g), anhydrous potassium carbonate (0.67 g), potassium iodide (0.07 g), cupuric oxide (0.02 g) and 7 ml of dimethyl formamide, was added 2-(1-bromoethyl)-5-ethoxy-1,3,4-thiadiazole (0.95 g) under stirring, and further stirred at 80° C. for one hour. After cooling and pouring water, the resulting solution was extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under a reduced pressure and the residue was purified on column chromatography to obtain 0.84 g of the compound (No. 1) described in Table 1.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>C(C(C)=O)C(C)C.O>[C:22]([C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[CH2:19][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[O:6])#[N:23]
Reactant: N#Cc1ccccc1CBr
Reactant: O=C1NCCS1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: N#Cc1ccccc1CN1CCSC1=O
Reaction time: 0.5 h

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g (0.081 mol) of potassium carbonate, 1.8 g (0.018 mol) of potassium hydrogen carbonate, 0.5 ml (0.027 mol) of water and 6.47 g (0.033 mol) of 2-bromomethylbenzonitrile in 30 ml of methyl isobutyl ketone is refluxed for 5 hours, then cooled down. After adding 30 ml of water the mixture is stirred for 30 minutes, the insoluble precipitate is filtered off, washed twice with 10 ml of water each and dried. After recrystallizing 4.71 g of crude product from 20 ml of ethanol under simultaneous clarification with activated carbon 3.39 g (51.8%) of white, crystalline title compound are obtained, m.p.: 116°-117° C.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([O:20]C)=[O:19])=[CH:10]1>CO.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18]([OH:20])=[O:19])=[CH:10]1
Reactant: COC(=O)c1cn(-c2ccccn2)c2ncccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2ccccn2)c2ncccc12
Temperature: 90 °C

Procedure:
Potassium hydroxide (11.30 mg, 0.201 mmol) was added to a solution of methyl 1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (10.2 mg, 0.040 mmol) in MeOH (67.1 μl) and water (67.1 μl) at RT. The mixture was heated at 90° C. for 2 h. The organic layer was extracted into ethyl acetate after acidifying the mixture with 0.5 N citric acid. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:29][C@@:30]2([CH3:33])[CH2:32][O:31]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:29][C@:30]1([CH2:33][O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH2:32][O:31]1
Reactant: CC(=O)Nc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To 2-acetamidophenol (90.5 mg, 0.598 mmol) and cesium carbonate (234 mg, 0.718 mmol) was added [(2R)-2-methyloxiranyl]methyl 4-methylbenzene-sulfonate (145 mg, 0.598 mmol) dissolved in DMF (1 ml). The mixture was stirred at room temperature for four hours and then partitioned between ethyl-acetate and water. After extraction the combined organic phases were dried and concentrated in vacuo. The residue was purified on silica (Heptane/EtOAc 3:1-2:1) to give 63 mg (48%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:21]
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C(C)(C)C)n1
Yield: 87 %

Procedure:
To a stirred and cooled (0° C.) solution of 6-methylpyridin-2-amine (25.00 g, 231.17 mmol) in dichloromethane (250 mL), were added triethylamine (41.81 mL, 300 mmol) and pivaloyl chloride (33.45 g, 277.4 mmol). The reaction mixture was allowed to room temperature and stirred for further 5 hrs. The reaction mixture was quenched with 150 mL of saturated solution of sodium bicarbonate, followed by the addition of 100 mL of brine. The organic phase was separated and dried over magnesium sulphate, filtered and concentrated in vacuo yielding to a yellow solid. The crude product was redissolved in 1 L of dichloromethane, to which were added 100 g of silica. The reaction mixture was stirred for 5 mns at room temperature and filtered yielding to 2,2-dimethyl-N-(6-methylpyridin-2-yl)propanamide as a solid [40.9 g, yield 87%; HPLC/MS: m/z=193 (M+H); logP(HCOOH)=1.20].
Reaction SMILES: O[CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.[Cl:12][C:13]([Cl:28])([Cl:27])[CH2:14][O:15][C:16](=[O:26])[NH:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]1([CH2:19][O:18][N:17]([CH2:2][C@@H:3]2[O:7][CH2:6][C@@H:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]2)[C:16]([O:15][CH2:14][C:13]([Cl:12])([Cl:27])[Cl:28])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Reactant: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 200.3 %

Procedure:
To a 0° C. solution, under argon, of 1.0 g of product from Example 6, 1.69 g of product from Example 70, 1.49 g of triphenylphosphine and 5.4 ml of tetrahydrofuran is added 0.988 g of diethyl azodicarboxylate in 1.4 ml of tetrahydrofuran. The reaction is stirred at room temperature for 48 hours, filtered and the filtrate concentrated in vacuo to give 5.18 g of thick oil. The oil is purified by chromatography (Silica Gel: 15-25% ethyl acetate/hexane) to give 0.805 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11](OCC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Clc1ncnc2[nH]ccc12
Product: CCOC(OCC)n1ccc2c(Cl)ncnc21
Reaction time: 63 h
Yield: 94 %

Procedure:
To a 1 liter round bottom flask equipped with a stir bar, condenser and nitrogen inlet was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 31.0 g, 0.202 mol) and triethyl orthoformate (330 ml, 2.00 mol, 10.0 equiv). The reaction mixture was warmed to reflux to generate a clear solution. The reaction was checked after 63 hours by HPLC. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel flash column chromatography eluted with a 20% to 25% ethyl acetate/hexane (v/v) gradient (TLC conditions: 30% ethyl acetate/hexane) to afford 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3b, 48.56 g, 51.65 g theoretical, 94% yield) as a light yellow oil. For 3b: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.68 (s, 1H), 7.79 (d, 1H, J=3.8 Hz), 6.75 (s, 1H), 6.72 (d, 1H, J=3.8 Hz), 3.68 (dd, 2H, J=9.4, 7.2 Hz), 3.54 (dd, 2H, J=9.4, 7.2 Hz), 1.11 (t, 6H, J=7.2 Hz); C11H14ClN3O2 (MW, 255.70), LCMS (EI) m/e 182/184 (M++H for corresponding 7-formylation product of 1) and 154/156 (M++H for 1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (5 g) and 5-cyclopropyl-1H-pyrazol-3-amine (5 g) in acetonitrile (40 mL) with diisopropylethylamine (6 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 5 g desired product. MS (electrospray): 280 (M+1) for C11H10ClN5O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.5 (d, 1H) 6.9 (d, 1H) 6.5 (s, 1H) 1.9 (m, 1H) 1.0 (m, 2H) 0.70 (m, 2H).