Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[Cl-].[NH4+].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>CN(C=O)C.C(N(CC)CC)C.CCOC(C)=O>[CH3:33][O:32][C:28](=[O:31])[CH:29]=[CH:30][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(C(CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one ((example 74, step 5), 300 mg) in DMF (3 mL) tetrakis(triphenylphosphine)palladium (130 mg), methyl acrylate (0.103 mL) and triethylamine (0.16 mL) were added. The reaction mixture was stirred at 100° C. overnight, was cooled to room temperature and diluted with EtOAc and a saturated solution of ammonium chloride. The phases were separated and the inorganic one extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield the title compound (62 mg, 20%) as a yellow oil, MS (ESI+): m/z=400.1912 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) is heated at 80°-90° C. overnight. The reaction mixture is poured into water (200 ml) NH4OH (1 ml), and the mixture is extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers are combined, dried over MgSO4 and evaporated. The residue is crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191°-192° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OCCOCCOCCN1CCOCC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1CCOCC1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a solution of 989 mg of 2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethanol in 2.8 mL of anhydrous THF was added 1.04 mg of sodium. After heating at 40° C. for 2 hours 15 minutes, 793 μL of tert-butyl acrylate were added. After heating for a further two hours at 40° C., the reaction mixture was left for 20 hours at room temperature and then concentrated under reduced pressure and purified by flash chromatography on silica (Merck SuperVarioPrep 70 g column, Si60 15-40 μm), using a gradient of 0 to 6% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 1 g of tert-butyl 3-{2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethoxy}-propanoate were obtained. LC/MS (E): tr (ELSD)=0.59 min; [M+H]+: m/z 348
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH:17]=[O:18])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.O.I([O-])(=O)(=O)=[O:26].[Na+]>C(Cl)(Cl)(Cl)Cl.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:19])[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([OH:26])=[O:18])[CH2:12][CH2:11]1)=[O:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(CC[C@H]1CC[C@H](CC(=O)O)CC1)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
0.66 g (2.3 mmol) of trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester were dissolved in 2 mL of CCl4, 2 mL of acetonitrile and 3 mL of water. To this mixture were added 2.4 mg (0.012 mmol, 0.01 eq) of anhydrous ruthenium (III) chloride, followed by 2.04 g (9.5 mmol, 4.1 eq) of sodium metaperiodate in small portions. Stirring was continued at RT for 2 h, the mixture was filtered and partitioned between CH2Cl2 and water. The organic phase was washed with water and dried over magnesium sulfate. Column chromatography of the crude product with a gradient of n-heptane: EtOAc 1:4 to 1:1 gave 430 mg (62%) of trans-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-acetic acid as colorless oil, MS: 317 (M+NH4+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN1C(=O)CCC1.O>[Cl:14][C:15]1[N:16]=[C:17]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:18]2[S:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 315 %

Procedure:
A stirred suspension of NaH (29.7 mg, 0.74 mmol) in dry NMP (3.5 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (108.2 mg, 0.74 mmol) and stirred at room temperature for 30 min under Argon. The reaction mixture was added to a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (39.6 mg, 0.19 mmol) in dry NMP (4 mL) and heated at 50° C. for 5 h. The resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1) to give the product as a white solid (189 mg, 81%):
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=3)[CH:12]=[N:11]2)=[CH:7][CH:6]=1>O.CCO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=3)[CH:12]=[N:11]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1csc(-c2cnn(Cc3ccc(OC)cc3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3nc(C(=O)O)cs3)cn2)cc1
Temperature: 50 °C
Yield: 88.3 %

Procedure:
According to Scheme 1 Step 6: A solution of NaOH (38.4 mmol, 12.8 mL) in water (3 M) was added at 0° C. to a solution of ethyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4 mmol, 5.28 g) in EtOH (38 mL) and the reaction mixture was heated at 50° C. overnight. After evaporation of the solvent, the crude residue was partitioned between a solution of NaOH (1 M) and EtOAc. After extraction, the organic phase was washed with a solution of NaOH (1 M). The aqueous phase was then acidified and the beige precipitate formed was filtered off, washed with water and dried to yield 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (13.6 mmol, 4.29 g, 88%) as a beige solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]([CH2:31][CH3:32])[C:20]3[C:25]([C:26]=2[C:27]#[N:28])=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[CH:21]=3)=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])(=O)C.O.[OH-].[Li+].C(OCC)(=O)C>C1COCC1>[C:27]([C:26]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=2)[N:19]([CH2:31][CH3:32])[C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([N:7]([CH2:6][CH2:5][OH:4])[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:17][CH:16]=1)#[N:28]
Reactant: CCn1c(-c2ccc(N(CCOC(C)=O)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(-c2ccc(N(CCO)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A mixture of N-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water is warmed to 60° C. overnight. The mixture is cooled and poured into ethyl acetate (50 mL). This is washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid is triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:26][C:27]1[CH:32]=[C:31](CCl)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[CH2:12][CH2:13]2)[CH:30]=[CH:29][N:28]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N,N-dimethylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1.C(O)(=O)C>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:3])[CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1
Reactant: CNC1C=Cc2cc(Cl)ccc2CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)C1C=Cc2cc(Cl)ccc2CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
7.7 ml of an aqueous solution of 40% formaldehyde and then 4.5 g of sodium cyanoborohydride were added to a mixture of 4.7 g of 2-chloro-7-methylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride in 47 ml of acetonitrile and the mixture was stirred for 15 minutes at room temperature. Acetic acid was added to the reaction mixture until the pH was 7 and the mixture was stirred at room temperature for 45 minutes. The mixture was evaporated to dryness under reduced pressure to obtain 2.6 g of 2-chloro-7-dimethylamino-6,7-dihydro [5H] benzocycloheptene in the form of an oil. Addition of a solution of fumaric acid in methanol yielded 3.3 g of the fumarate of the said product melting at 160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].C(OCC)(=O)C.[CH3:30][N:31](C)C(=O)C>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:9]2=[C:10]([C:30]#[N:31])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCC(C)C

Procedure:
To a mixture of 7-bromo-2,3-dichloro-4-hydroxy-1-(3-methyl-butyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (1.16 g, 2.74 mmol), 1,1′-bis(diphenylphosphino)ferrocene (228 mg, 0.411 mmol), zinc dust (32.1 mg, 0.493 mmol), and zinc cyanide (290 mg, 2.47 mmol) in N,N-dimethylacetamide (8.7 mL) was added tris(dibenzylideneacetone)dipalladium(0)(188 mg, 0.21 mmol). The reaction mixture was heated at 120° C. for 1.5 hours before ethyl acetate (100 mL) was added. The organic solution was washed with saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-30% ethyl acetate in hexanes to produce 0.65 g of the title compound as a light yellow solid. MS: (+) m/z 370.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.Cl.Cl.[CH3:20][N:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:26]2[CH:25]=[N:24][C:23]([N:21]([CH3:22])[CH3:20])=[CH:28][CH:27]=2)[CH:3]=[N:4][CH:5]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)c1ccc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cn1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (50 mg, 0.18 mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid 2HCl salt (55 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %), acetonitrile (2 mL) and 0.5 M sodium carbonate (1.3 mL, 0.66 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-82:18, biotage 25+S) followed by preparative tlc (CH2Cl2, MeOH, 9:1) to furnish the title compound as an off white solid (6 mg, 9%), LC-MS (ESI, 4 min) Rt 1.28 min, m/z 360 (100%, [M+H]+); m/z (ESI) C17H22N5OCl requires 359.1513, found [M+H]+ 359.1511.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:23]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(NCc2ccccc2)cc1Cl
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccccc1)c1ccc(F)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (1.47 mL, 8.45 mmol) and then methyl bromoacetate (1.29 g, 8.45 mmol) were added to a solution of N-benzyl-3-chloro-4-fluoroaniline (7-1, 1.00 g, 4.23 mmol) in DMF (7 mL), and the resulting mixture was stirred at 50° C. for 2 h, 60° C. for 3 h, and then 50° C. for 18 h. Methyl bromoacetate (0.4 mL, 4 mmol) was added and mixture was heated to 60° C. for 7 h and then 50° C. for 18 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (3×100 mL), H2O (100 mL), and brine (50 mL). The reaction was concentrated and purified residue by flash column chromatography (SiO2, 0-20% EtOAc/hexanes gradient) to provide methyl N-benzyl-N-(3-chloro-4-fluorophenyl)glycinate (7-2). 1H NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 6.97 (dd, J=8.9, 8.9 Hz, 1H), 6.69 (dd, J=6.1, 3.1 Hz, 1H), 6.50 (ddd, J=8.9, 3.4, 3.4 Hz, 1H), 4.59 (s, 2H), 4.05 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24].OC1N(C2C=CC=CC=2[N+:43]([O-:45])=[O:44])C(=O)N(CC2C=CC=CC=2)C(=O)C=1C(OCC)=O.C1CCN2C(=NCCC2)CC1.NCC(O)=O.Cl>C(O)C>[OH:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[N+:43]([O-:45])=[O:44])[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]
Reactant: CCOC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: NCC(=O)O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Temperature: 170 °C

Procedure:
N-{[6-Hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture of ethyl 6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (59 mg, 0.14 mmoles), DBU (80 mg, 0.52 mmoles) and glycine (40 mg, 0.53 mmoles) in ethanol (3 mL) was sealed in a flask and heated in a microwave reactor at 170° C. for 1 hour. The reaction mixture was poured into 1 molar hydrochloric acid and extracted with dichloromethane (×2) and washed with 1 molar hydrochloric acid. The title compound was obtained by purification by preparative HPLC (10-80% acetonitrile-water-0.1% TFA)(17 mg, 28%) 1H NMR (400 MHz, DMSO-d6) δ ppm 13.14 (br. s., 1 H), 10.04 (br. s., 1 H), 8.25 (dd, J=8.21, 1.14 Hz, 1 H), 7.93 (dt, J=7.71, 1.26 Hz, 1H), 7.71-7.81 (m, 2 H), 5.06 (s, 2 H), 4.14 (d, J=5.56 Hz, 2 H)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:10][C:11]=2/[CH:12]=[N:13]/[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[S:10][C:11]=2[C:12]2[N:13]([S:14]([N:17]([CH3:18])[CH3:19])(=[O:16])=[O:15])[CH:39]=[N:38][CH:37]=2)=[CH:26][CH:27]=1
Reactant: CN(C)S(=O)(=O)/N=C/c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CN(C)S(=O)(=O)n1cncc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
A solution of N′-{(1E)-[4-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-thiazol-5-yl]methylene}-N,N-dimethylsulfamide (148 mg, 0.352 mmol), p-tolylsulfonylmethyl isocyanide (75.5 mg, 0.387 mmol) and potassium carbonate (146 mg, 1.05 mmol) in DME (2.50 mL) was heated at 78° C. for 2 hours. The reaction was diluted with DCM (10 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give 50 mg of 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide. LC/MS (FA) ES+ 460. (Some of the deprotected product, 4-(4-chlorobenzyl)-5-(1H-imidazol-5-yl)-2-(pyridin-4-yl)thiazole, was also obtained (19 mg). This material was combined with the material obtained in the following deprotection step.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH3:10][C:11]1[CH:12]=CC(C)=[CH:15][CH:16]=1.O1CCOC1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:10][C:11]1([CH3:12])[CH:16]=[CH:15][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=2[O:9]1
Reactant: Cc1ccc(C)cc1
Reactant: N#Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCO1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1
Temperature: 140 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
Under an argon atmosphere, 4-cyanophenol (0.186 g, 1.56 mmole), p-xylene (1 mL), the dioxolane prepared above (0.2 g, 1.56 mmole), and pyridine (0.12 mL, 1.56 mmole) were combined in that order. The mixture was heated to 140° C. (internal temperature). After 24 hours, the reaction mixture was diluted with ethyl acetate (3 mL) and washed with 10% hydrochloric acid. The organic layers were collected, washed with 1N sodium hydroxide, brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a dark brown oil (0.085 g, 30% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH2:11]([PH:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([P:14]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1)([CH2:15][CH2:16][CH3:17])=[O:18])[CH2:12][CH3:13]
Reactant: CCC[PH](=O)CCC
Reactant: COc1cc(Br)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CCCP(=O)(CCC)c1ccc(N)c(OC)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl.[Cl:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.[Na+].[I-]>[ClH:11].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCC1
Reactant: Cc1cccc(C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: Cc1cccc(C)c1OCCN1CCCC1
Yield: 64.8 %

Procedure:
46.7 g (0.38 mole) of 2,6-dimethylphenol, 65.0 g (0.38 mole) of N-(2-chloroethyl)pyrrolidine hydrochloride, 210.1 g (1.52 mole) of potassium carbonate and 2 g of NaI in 300 ml of ethyl methyl ketone were refluxed for 48 h. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between water and ether, the organic phase was separated off, washed with water and dried, and excess ethereal hydrogen chloride solution was added. The precipitated product was recrystallized from 10/1 ethyl acetate/isopropanol. 63 g of N-[2-(2,6-dimethylphenoxy)ethyl]pyrrolidine hydrochloride were obtained.