Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11.53 g), benzyl bromide (18 ml), potassium carbonate (21.12 g) and N,N-dimethylformamide (300 ml) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, then washed successively with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (13.52 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 71–72° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:17]=1[NH2:18].[Cl-].[NH4+]>S(Cl)(Cl)=O.N1C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH:18][C:17]1[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCC(Br)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(Br)C(=O)Nc1c(OC)cc(OC)cc1OC
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
2-Bromodecanoic acid (1 g, 3.8 mmol) was heated under reflux in thionyl chloride (10 ml) for 1 hour. The thionyl chloride was evaporated and the residue was dissolved in dry ether (10 ml) and added dropwise to a solution of 2,4,6-trimethoxyaniline (0.7 g, 3.8 mmol) in pyridine (20 ml) at 0° C. and the mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with ethyl acetate (60 ml). The combined organics were extracted with water and brine and dried and concentrated. Recrystallization from isopropyl ether afforded 1.1 g (65%) of the title compound, m.p. 109°-110° C. This material was used directly in the next step.
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[C:35]1(=[O:45])[C@@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[C:37](=O)[O:36]1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=[C:37]2[C@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@H:43]2[C:35]([OH:45])=[O:36])=[CH:33][CH:34]=1
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@H]3CCCC[C@H]3C(=O)O)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and racemic cis-hexahydroisobenzofuran-1,3-dione followed by the hydrolysis according to Example 111. MS (ESI): mass calcd. for C29H31N3O3, 469.24; m/z found, 470.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.50 (s, 1H), 8.02 (d, J=8.1, 1H), 7.74 (d, J=9.0, 1H), 7.69 (d, J=8.1, 1H), 7.36 (dd, J=9.0, 2.3, 1H), 7.25 (d, J=2.2, 1H), 7.17 (d, J=8.0, 2H), 7.00 (d, J=8.1, 2H), 5.77 (d, J=16.9, 1H), 5.71 (d, J=17.0, 1H), 5.36-5.19 (m, 2H), 3.63 (dt, J=12.1, 3.7, 1H), 2.90 (d, J=3.7, 1H), 2.45 (s, 3H), 2.37-2.25 (m, 4H), 2.19 (d, J=14.2, 1H), 2.05 (d, J=12.9, 1H), 1.96 (t, J=12.1, 1H), 1.82-1.72 (m, 1H), 1.72-1.63 (m, 1H), 1.59-1.35 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=O)[NH:9][N:10]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[NH4+]>CC(C)=O.O>[Cl:18][C:8]1[N:9]=[N:10][C:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1Cc1ccc(=O)[nH]n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1Cc1ccc(Cl)nn1

Procedure:
2,3-Dihydro-6-(2-methylbenzyl)pyridaz-3-one (prepared as described above; 36 g.) and phosphorus oxychloride (120 ml.) were heated together on a steam bath to 90° C. The dark red solution thus obtained was immediately cooled to 10°-15° C., diluted with acetone (125 ml.) and added to a stirred solution of acetone and aqueous ammonium hydroxide solution (s.g. 0.880) (1:1; 1000 ml.) maintained at a temperature of from 0° to 20° C. by strong cooling. The mixture was then diluted with water (1000 ml.). A light brown coloured solid was precipitated, filtered off, dried and dissolved in toluene (200 ml.). The toluene solution was filtered and the filtrate evaporated to dryness to give 3-chloro-6-(2-methylbenzyl)pyridazine (34 g.) in the form of an off-white coloured solid, m.p. 73.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:12]
Reactant: O=CO
Reactant: Nc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CNc1ccc2c(c1)CCC2
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 5-aminoindane (7.53 g, 56.5 mmol) in DMF (100 mL) was added formic acid (2.2 mL, 58.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.94 g, 57 mmol) and diisopropylethylamine (19.7 mL, 0.11 mol). The resulting solution was stirred overnight and then partitioned between saturated aqueous citric acid (100 mL) and ethyl acetate (200 mL). The organic layer was separated and washed with aqueous sodium bicarbonate solution (100 mL) and water (3×100 mL), then concentrated under reduced pressure to give the formamide as a thick oily solid (8.5 g, 93%)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH3:24][NH:25][CH3:26].O>CCO>[CH3:24][N:25]([CH3:26])[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 28.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and dimethylamine (0.23 mL, 1.3 mmol, 5.6 M in EtOH) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., water (3 mL) was added. The resulting suspension was filtered dried under high vacuum to afford a crude solid, which was purified by silica gel chromatography (5-40% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound. MS: (+) m/z 324.03 (M+1).
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[N:7]([CH3:17])[C:6]=1[C:18]1[O:22][C:21]([CH3:23])=[N:20][N:19]=1)(=O)C.C[O-].[Na+].O.Cl>CO>[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])(=[O:16])[N:7]([CH3:17])[C:6]=1[C:18]1[O:22][C:21]([CH3:23])=[N:20][N:19]=1
Reactant: CC(=O)OC1=C(c2nnc(C)o2)N(C)S(=O)(=O)c2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nnc(C2=C(O)c3ccccc3S(=O)(=O)N2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of product (b) (2.218 g) in methanol (20 ml) was added 28% sodium methoxide (1.28 ml). After stirring at room temperature for 30 minutes, the solvent was stripped off and water (30 ml) was added. With vigorous stirring the pH was adjusted to ca. 1.5 with 6N HCl and the resulting solid granulated for 1 hour, filtered off, washed with water, and dried in vacuo to give compound (c), 1.903 g, 98% yield.
Reaction SMILES: [CH:1]([S:4]([NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].NC1CCC(C(OC)=O)CC1.CC(S(Cl)(=O)=O)C.[NH2:35][C:36]1[C:41]([NH2:42])=[CH:40][CH:39]=[C:38]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[N:37]=1>>[F:50][C:44]1[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:37]=[C:36]2[N:35]=[C:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:9][CH2:10]3)[NH:42][C:41]2=[CH:40][CH:39]=1
Reactant: Nc1ccc(-c2ccc(F)cc2F)nc1N
Reactant: CC(C)S(=O)(=O)NC1CCC(C(=O)O)CC1
Agent: CC(C)S(=O)(=O)Cl
Agent: COC(=O)C1CCC(N)CC1
Product: CC(C)S(=O)(=O)N[C@H]1CC[C@H](c2nc3nc(-c4ccc(F)cc4F)ccc3[nH]2)CC1

Procedure:
4-isopropylsulfonylaminocyclohexanecarboxylic acid as prepared easily from methyl 4-aminocyclohexanecarboxylate with 2-propanesulfonyl chloride, and 2,3-diamino-6-(2,4-difluorophenyl)pyridine were allowed to undergo ring-closure condensation under the same conditions as described in Example 1-3), followed by separatory purification on a collective thin-layer chromatograph (chloroform:methanol=20:1) to give the title compounds.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1c(C)nc2sccc2c1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.078 g; 0.250 mmol), LHMDS 1N in THF (0.276 mL; 0.276 mmol), 1-iodopropane (0.041 mL; 0.420 mmol) in DMF (3.6 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.052 g (59%) of the title compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CO.O>[CH2:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: NCC(=O)O
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNCC(=O)O
Yield: 41.6 %

Procedure:
A! A 32% solution of sodium hydroxide (123 ml) was added to a mixture of glycin (50 g, 0.66 mole) and butyl bromide (75 ml, 0.66 mole) in methanol (600 ml) and water (600 ml), the reaction mixture was refluxed for 24 hours, then the solvend was evaporated under vacuum. The crude was dissolved in ethanol, the salts were filtered off 3 times, and the solvent was evaporated under vacuum. The resulting crude was purified by flash chromatography (eluent: chloroform/methanol/concentrated ammonia 6:4:0.5) yielding 36 g of N-butyl-glycine.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(CBr)Nc1ccc(F)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(F)cc1C(=O)O
Temperature: 120 °C
Yield: 74.9 %

Procedure:
A solution of 2-(bromoacetamido)-5-fluorobenzoic acid from Example 19 (22.36 g, 91 mmol) and aniline (21 mL, 230 mmol) in dry DMF (150 mL) was heated at 85° C. for 5 hours. TLC showed indicated the presence of unreacted starting. Additional aniline (5 mL, 52 mmol) was added, and the solution was heated at 120° C. for 30 hours. After cooling, the reaction mixture was poured into ice-water (800 mL) and aqueous 5% KOH (100 mL) was added to adjust the pH to 10-11. The excess aniline was removed by extraction with CH2Cl2 (3×400 mL) and the aqueous layer was separated and acidified with aqueous 20% HBr. The resulting precipitate was collected, washed with water and dried, yielding 19.64 g (74.6%) of the title compound as white crystals, mp 194°-195° C.; 1H NMR (acetone-d6) δ 11.87 (s, 1H), 8.88 (dd, J=5.2, J=9.6, 1H), 7.71 (dd, J=3.2, J=9.2, 1H), 7.45-7.39 (m, 1H), 7.14-7.10 (m, 2H), 6.68-6.64 (m, 3H), 3.92 (s, 2H); 13C NMR (acetone-d6) δ 171.30, 168.14, 163.22, 157.97 (d, J=241.3), 148.97, 138.66, 129.82, 122.60 (d, J=7.1), 121.90 (d, J=21.9), 118.63, 117.78 (d, J=24.0), 113.67, 50.07; MS (EI, m/z) 288.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: CO
Product: COCc1cc(C(=O)OC)ccc1Br
Yield: 94 %

Procedure:
A solution of methyl 4-bromo-3-(bromomethyl)benzoate (38 g; 122 mmol) in MeOH (1.1 L) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (30 g, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 8.06-8.05 (m, 1H), 7.83 (m, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].[Cl:12][C:13]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].Cl>C(O)C.O>[Cl:12][C:13]1[N:20]=[C:19]([S:11][C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(Cl)nc1Cl
Reactant: Fc1ccc(S)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(Sc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of ethanol is added, under nitrogen, to a solution of 698 μL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of ethanol. The reaction medium is stirred at room temperature for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6-dichloronicotinonitrile in 30 mL of ethanol. The reaction medium is stirred for 2 hours at 0-5° C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the producted is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2-chloro-6-(2,4-difluorophenylthio)-nicotinonitrile in the form of a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[O-:20][C:21]#[N:22].[K+]>C(O)C.O>[NH:1]([CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:21]([NH2:22])=[O:20]
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCCC(NC(N)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A stirred solution of diethyl 2-aminononanedioate (10 g) in ethanol (77 ml) was cooled in ice-water and treated with 2N hydrochloric acid (38.6 ml) followed by a solution of potassium cyanate (6.255 g) in water (20 ml). The cooling bath was removed and the suspension was stirred for 7 hours at room temperature then set aside overnight. The ethanol was evaporated in vacuo and the residue was shaken with water and chloroform; the chloroform phase was separated, washed with water and dried (MgSO4), and the chloroform was evaporated to give an oil which was heated on the steam bath for 6 hours. The resulting oil crystallised on standing at room temperature. The crystals were stirred with ether and collected, affording pure diethyl 2-ureidononanedioate, m.p. 79°-80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[C:16]#[CH:17]>C(OCC)(=O)C.O>[CH2:15]([NH:18][S:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:13])=[O:12])[C:16]#[CH:17]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: C#CCN
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a cooled (0° C.) suspension of 4-nitrophenylmethanesulfonylchloride (0.510 g, 2.16 mmol) in ethyl acetate (3.0 mL) was added a solution of propargyl amine (1.0 mL, 14.5 mmol) in water (1.0 mL). The reaction mixture was stirred for 30 minutes and then diluted with ethyl acetate (30 mL) and washed with 1N HCl (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide 4-(prop-2-ynylaminosulfonylmethyl)nitrobenzene as a tan solid (0.437 g), which was used without further purification. 1HNMR (CDCl3): δ 8.25 (d, J=8.7 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 4.48 (s, 3H), 3.98 (dd, J=2.7 and 6.3 Hz, 2H), 2.48 (t, J=2.7 Hz, 1H); LCMS: purity: 99%; MS (m/e): 253 (M−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:18][CH2:17][C:16]([F:25])([F:24])[F:15])[CH:6]=1)[CH3:2]
Reactant: CS(=O)(=O)OCCC(F)(F)F
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OC)c(OCCC(F)(F)F)c1

Procedure:
The mixture of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.75 g, 8.92 mmol), methanesulfonic acid 3,3,3-trifluoro-propyl ester (2.06 g, 10.7 mmol) and anhydrous K2CO3 (2.49 g, 17.8 mmol) in acetone (20 mL) is heated with stirring at reflux temperature overnight. After cooling, the mixture is diluted with AcOEt followed by washing of the organic phase with 2N aqueous NaOH and brine. The organic layer is dried over Na2SO4 and evaporated, and the crude product is purified by silica gel chromatography (eluent: hexane/AcOEt 5:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.59. MS: 293.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (t, 3H), 2.74 (m, 2H), 3.96 (s, 3H), 4.33 (m, 2H), 4.40 (m, 2H), 6.94 (m, 1H), 7.59 (s, 1H), 7.77 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:13]([O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)[CH3:14]
Reactant: O=Cc1c(O)ccc(F)c1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1ccc(F)c(F)c1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 2,3-difluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), iodoethane (6.679 g; 42.80 mmol), and K2CO3 (3.551 g; 25.70 mmol) in anh. DMF (60 ml) was heated to 80° C., under nitrogen, for 1.5 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 6-ethoxy-2,3-difluorobenzaldehyde as a yellow solid. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 39.5 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (2.8 g, 8.0 mmols), ethyl 3-bromopropionate (2.1 ml, 16 mmols), potassium carbonate (1.1 g, 8.0 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 3-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminopropionate (1.42 g, 39.6%).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OC)(C)(C)C>[CH3:23][S:24]([O:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCC[C@@H](O)c1ccc(C(=O)OC)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1

Procedure:
To a solution of (R)-methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl t-butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20° C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=CC=3)[O:43]CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:43][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ); 7.51, 7.36–7.23, 6.98–6.90, 5.37, 4.69, 4.32, 2.66, 2.51, 2.31, 1.29–1.17; HRMS (EI) calcd for C23H23Cl2N3O 427.1218, found 427.1224.