Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]([CH:21]([C:20]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CC(=O)OCC
Reactant: CCCCCCCCCCCC1=NCCN1CCO
Product: CCCCCCCCCCC(C1=NCCN1CCO)C(C)C(=O)OCC
Yield: 99.7 %

Procedure:
Fifty-three and seven tenths g (53.7 g, 0.2 mol) of 1-(2-hydroxyethyl)-2-undecyl-2-imidazoline was melted, and 60 g (0.6 mol) of ethyl acrylate was added. The mixture was reacted at a temperature of 60°-65° C. for 4 hr. in a substantially anhydrous condition. After the reaction, the excess ethyl acrylate was removed by vacuum-topping the reaction mixture at a temperature of 30°-40° C. Seventy-three and a half g (73.5 g) of 1-(2-hydroxyethyl)-2-(α-ethoxycarbonylethyl-undecyl)-2-imidazoline was obtained as a slightly yellow viscous liquid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH2:11]2)[C:5]=1[CH3:22])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]2[S:21](=[O:28])[C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH2:11]2)[C:5]=1[CH3:22])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccnc(C2Cn3c(nc4ccccc43)S2)c1C
Solvent: ClCCl
Product: CCSc1ccnc(C2Cn3c(nc4ccccc43)S2=O)c1C

Procedure:
A solution of 2-(4-ethylthio-3-methylpyrid-2-yl)-2,3-dihydrothiazolo[3,2-a]benzimidazole (0.01 mole) is dissolved in CH2Cl2 solution (100 ml) at 0° C. and treated with m-chloroperoxybenzoic acid (0.01 mole) for 0.5 hours. The solution is then washed with sodium carbonate solution and dried (MgSO4). Purification by chromatography on silica gives the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19]>C(O)C>[NH2:19][C:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccccc2)C1
Yield: 104.5 %

Procedure:
A solution of 5-phenylcyclohexane-1,3-dione (5.0 g), ammonium acetate (6.1 g) in ethanol (100 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate and water. Precipitated crystals were filtered, washed with water and dried to give pale yellow crystals of 1-amino-5-phenylcyclohexen-3-one (5.2 g).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C@H:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]5)[N:13]=3)=[CH:11][C:6]=2[O:5][CH2:4]1.I[CH3:39].[Cl-].[NH4+]>CN(C=O)C>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([N:18]([CH3:39])[CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C@H:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]5)[N:13]=3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nccc(-c4ccc5c(c4)OCO5)n3)ccc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nccc(-c4ccc5c(c4)OCO5)n3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 264.6 %

Procedure:
To a suspension of sodium hydride (8.4 mg of a 60% dispersion, 0.210 mmol) in DMF (4 mL) cooled in an ice-bath, was added ethyl [(1S)-5-(3-{[4-(1,3-benzodioxol-5-yl)-2-pyrimidinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 291, 50 mg, 0.105 mmol). The mixture was stirred for 15 min after which iodomethane (61 mg, 0.421 mmol) was added dropwise. The mixture was then stirred at rt for 16 h. A solution of ammonium chloride (10% in water) was added to the reaction mixture after which the mixture was concentrated under reduced pressure and brought to basic pH using a saturated solution of NaHCO3. The mixture was extracted with EtOAc (2×). The combined organic layers were washed with water and brine, dried, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (1:2 EtOAc/hexanes) to give the product (136 mg, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, 3H), 1.70-1.79 (m, 1H), 2.15-2.20 (m, 2H), 2.33-2.51 (m, 2H), 2.70 (dd, 1H), 2.82-2.95 (m, 2H), 3.30 (s, 3H), 3.53-3.64 (m, 1H), 3.71 (q, 2H), 4.13 (t, 2H), 4.22 (q, 2H), 6.01 (s, 2H), 6.65 (d, 1H), 6.75 (s, 1H), 6.90 (d, 2H), 7.05 (d, 1H), 7.62 (d, 1H), 7.15 (s, 1H), 8.30 (d, 1H); LC-MS: RT=3.01 min, (M+H)+ 490.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[Cl:31])[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Cl
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Product: CN(Cc1ccccc1Cl)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 2-chlorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=528.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[N:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COc1ccc(CCNc2ccnc(Cl)n2)cc1OC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNc2nccc(NCCc3ccc(OC)c(OC)c3)n2)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
In a sealed flask, a mixture of 7 (744 mg, 2.53 mmol), methyl 4-(aminomethyl)benzoate (628 mg, 3.80 mmol) and i-Pr2NEt (882 μl, 5.07 mmol) in isopropanol (50 mL) was heated to 120-125° C. for 7 days (during this period of time an excess of methyl 4-(aminomethyl)benzoate was added to the reaction mixture). The reaction mixture was allowed to cool to the room temperature, concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95→10/90 plus several drops of NH4OH) to afford the title compound 8 (671 mg, 1.59 mmol, 63% yield) as an orange sticky solid.
Reaction SMILES: C([NH:4][CH:5]([CH:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])[C:6]([OH:8])=[O:7])(=O)C>Cl>[NH2:4][CH:5]([CH:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)C(C)NCc1ccccc1
Agent: Cl
Product: CC(NCc1ccccc1)C(N)C(=O)O

Procedure:
Example VII was repeated except that 2-acetamido-3-benzylaminobutyric acid was refluxed in 6M HCl to yield 2-amino-3-benzylaminobutyric acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:47][C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: C[C@@H](N)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 72 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and R-(+)-α-methylbenzylamine: yield 72%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
432 mg (3.22 mmol) of 2-(2-ethoxyethoxy)ethanol was dissolved in 40 ml of dichloromethane, and 0.6 ml (4.19 mmol) of triethylamine and 614 mg (3.22 mmol) of p-toluenesulfonyl chloride were added thereto. The mixture was stirred at room temperature for 15 hours. After the solvent was removed under reduced pressure, 40 ml of water was added thereto. The mixture was extracted with 30 ml of ethyl acetate. The solvent was removed under reduced pressure to give 760 mg (2.64 mmol) of the title compound in a yield of 82%.
Reaction SMILES: [Na].[CH:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][CH:3]=1>CC(C)=O.[Co]>[CH:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:8]3[N:9]=[C:8]4[N:11]=[C:10]([C:5]5[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=54)[N:11]=[C:10]4[NH:9][C:8]([C:6]5[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=54)=[N:11][C:10]4=[N:9][C:8]([C:6]5[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=54)=[N:11][C:10]=2[NH:9]3)[CH:7]=1
Reactant: N#Cc1ccccc1C#N
Agent: [Co]
Agent: [Na]
Solvent: CC(C)=O
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 210 °C
Reaction time: 5 h

Procedure:
A zeolite X powder including Co2+-phthalocyanine complex (CoPc) was prepared according to the following procedure. Specifically, a powder (product supplied by Tosoh Corporation) of zeolite X containing sodium ions (NaX) was prepared, and part of sodium ions (Na+) contained in the zeolite were exchanged with cobalt ions (Co2+) through ion exchange to yield NaX containing 0.95 percent by weight of Co2+ ions (Co—NaX). In acetone were stirred 108.96 g of the Co—NaX (containing 18 mmol of Co2+) and 0.127 mol of o-phthalonitrile for one hour, a volatile component was removed from the react ion mixture, and the residue was suspended in 250 mL of ethylene glycol. The suspension was combined with 15 mL of tri-n-butylamine ((n-Bu)3N), and the mixture was stirred at 210° C. for 5 hours to give a solid. The solid was purified through extraction sequentially with methanol, acetone, and pyridine in a Soxhlet extractor to remove unnecessary substances such as unreacted ligand contained in the solid and phthalocyanine that had formed outside the zeolite pores. The purified product was suspended in 400 mL of a saturated aqueous solution of sodium nitrate, followed by stirring for 24 hours, to remove unreacted cobalt ions that had remained without forming the complex through exchange with sodium ions. The resulting substance was washed with water, dried at 60° C., and thereby yielded a pale blue powder. The energy dispersive X-ray spectroscopy (EDX), ultraviolet-visible (UV/vis) absorption spectra, and diffuse reflection spectra of the powder verified that a target substance (CoPc@NaX) composed of NaX and cobalt phthalocyanine encapsulated in the NaX unit cell was obtained.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:24]#[N:25])(C)C>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)[C:24]#[N:25])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(F)cc1)c1ccc(S(N)(=O)=O)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-fluoro-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 83%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[O:27][C:26]([C:28]([O:30]CC)=[O:29])=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[N:6]=1.O.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc(Cn2cc(C3c4ccccc4C=Cc4oc(C)nc43)c(=S)[nH]c2=O)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(o1)C=Cc1ccccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the product from step (iii) (0.13 g) and lithium hydroxide monohydrate (0.042 g) in methanol (20 ml) and water (10 ml) was stirred at room temperature for 72 hours and heated at reflux for 1 hour. The solution was concentrated under reduced pressure and the residue partitioned between 2M hydrochloric acid and ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and the resultant solid collected by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@H:20]([OH:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(O)CO>C(OCC)(=O)C.[Cu]I.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@H:20]([OH:22])[CH3:21])[CH:6]=[CH:5]2
Reactant: Sc1ccc2cc(Br)ccc2c1
Reactant: C[C@H](O)c1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](O)c1ccccc1Sc1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 87.2 %

Procedure:
A mixture of 6-bromo-2-naphthyl hydrosulfide (Example 5 Step 2, 1.80 g, 7.53 mmol), (1S)-1-(2-iodophenyl)ethanol (1.82 g, 7.34 mmol), copper(I) iodide (70 mg, 0.37 mmol) and potassium carbonate (2.02 g, 14.6 mmol) was degassed then isopropyl alcohol (10 mL) and ethylene glycol (0.82 mL, 14.7 mmol) added. The reaction was heated to 80° C. overnight. The cooled reaction mixture was diluted with ethyl acetate (40 mL), filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a 10-20% ethyl acetate/isohexane gradient to give solid (1S)-1-{2-[(6-bromo-2-naphthyl)thio]phenyl}ethanol (2.30 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.94 (1H, s), 7.68 (1H, dd, J 1.4, 7.8), 7.64 (1H, d, J 8.7 Hz), 7.58-7.50 (3H, m), 7.43-7.39 (1H, m), 7.36 (1H, dd, J 1.4, 7.8 Hz), 7.30 (1H, dd, J 1.8, 8.6 Hz), 7.27-7.23 (1H, m), 5.44 (1H, q, J 6.3 Hz), 1.46 (3H, d, J 6.4 Hz); m/z (ES+) 341, 343 [(M-OH)+].
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])Cl)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl-].[NH4+]>O1CCCC1>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:14]1[CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]1[C:11]#[N:12]
Reactant: N#CCCN(Cc1ccccc1)CC(Cl)c1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC1CN(Cc2ccccc2)CC1c1ccccc1Br
Temperature: -70 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
The 90.2 g of product obtained in Step 3 are dissolved in tetrahydrofuran. The solution is cooled to -70° C. and 143 ml of a 2M solution of sodium hexamethyldisilazide are poured in dropwise. After 1 hour at -70° C. and then 12 hours at ambient temperature, the reaction mixture is poured into 300 ml of saturated aqueous ammonium chloride solution and then extracted with ether. The combined organic phases are washed and dried. After evaporating, 78.5 g of expected product are obtained in the form of a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[I-].ClCC[S+](C)C.O>C(O)(C)(C)C>[CH2:1]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[O:14])[CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)CCCl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1CCCCCC12CC2

Procedure:
To a suspension of potassium tert-butoxide (3.48 g) in tert-butanol (32 mL) was added cycloheptanone (1.9 mL) while stirring under nitrogen atmosphere, followed by stirring the mixture at room temperature for 0.5 hour. Then, to the reaction mixture was added (2-chloroethyl)-dimethylsulfonium iodide (3.7 g) in eight portions over 1.6 hours, followed by stirring the mixture at room temperature for 16.5 hours. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:15) to give spiro[2.6]nonan-4-one (1.40 g).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][CH2:5][C@@H:4]1[NH:8][C:9]([C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:10].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:23])[CH2:21][N:6]1[CH2:7][C@H:3]([OH:2])[C@@H:4]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5]1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: O=C(N[C@H]1CNC[C@@H]1O)c1ccc(Cl)s1
Agent: Cl
Product: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1

Procedure:
39.1 Using general procedure A 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-hydroxy-pyrrolidin-3-yl)-amide hydrochloride (example 22.5) was reacted with bromoacetic acid ethylester to give {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidin-1-yl}-acetic acid ethyl ester. Light yellow solid. MS 333.3 ([M+H]+)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:49]1[N:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[N:52]=[C:51]([CH2:59][C:60]([O:62][CH3:63])=[O:61])[CH:50]=1>O1CCCC1>[CH3:63][O:62][C:60](=[O:61])[CH2:59][C:51]1[N:52]=[C:53]([C:55]([F:57])([F:58])[F:56])[N:54]=[C:49]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:50]=1
Reactant: COC(=O)Cc1cc(O)nc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (213 mg, 1.06 mmol, Aldrich) in tetrahydrofuran (2.0 mL) was added Triphenylphosphine (0.284 g, 1.08 mmol), followed by diisopropyl azodicarboxylate (0.215 mL, 1.09 mmol). After 10 minutes, methyl [6-hydroxy-2-(trifluoromethyl)pyrimidin-4-yl]acetate (0.20 g, 0.85 mmol, from Step 1) was added. The reaction was stirred for 1 hour and solvent was removed in vacuo. Flash chromatography on a 40 g silica gel cartridge, eluting with a gradient from 0-20%) EtOAc in hexanes afforded product as a viscous oil (127 mg, 25%). LCMS (M+H)+: 420.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:18]C)=[C:14]([CH:17]=1)[C:15]#[N:16].B(Br)(Br)Br.CCOC(C)=O.O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: COc1ccc(-c2nc3ccccc3o2)cc1C#N
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cc(-c2nc3ccccc3o2)ccc1O
Reaction time: 4 h

Procedure:
To a solution of 5-(1,3-benzoxazol-2-yl)-2-methoxy benzonitrile (270 mg, 1.1 mmol) in CH2Cl2 (5 mL) at 0° C., was added BBr3 (1.0M solution in CH2Cl2, 430 μL, 4.4 mmol) dropwise. The reaction was stirred at it for 4 h. EtOAc (150 mL) was added, as well as H2O (30 mL). The organic layer was washed with brine (2×20 mL), dried (MgSO4), concentrated and the crude product was recrystallized in EtOAc to afford 5-(1,3-benzoxazol-2-yl)-2-hydroxy benzonitrile. MS (ESI) 237 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][NH:24][C:25](=[O:35])[CH2:26][N:27]2[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]2)=O)[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].C([NH+](CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:35][C:25]([CH2:26][N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[N:24][N:23]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(C(=O)NNC(=O)CN4C[C@@H](C)O[C@@H](C)C4)cc(Br)cc32)cc1
Agent: CC[NH+](CC)CC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5C[C@@H](C)O[C@@H](C)C5)o4)cc(Br)cc32)cc1
Temperature: 75 °C
Yield: 73.9 %

Procedure:
6-Bromo-N′-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazide (950 mg, 1.683 mmol) was dried over phosphorus pentoxide in a desicator overnight. 6-bromo-N′-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazide (950 mg, 1.683 mmol) and methoxycarbonylsulfamoyl)triethylammonium hydroxide (602 mg, 2.52 mmol) were suspended in anhydrous tetrahydrofuran (20 ml) and heated to 75° C. for 2 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane (15 ml) and saturated sodium bicarbonate solution (15 ml). The layers were separated (hydrophobic frit), the aqueous washed with further dichloromethane (5 ml) and the combined organics concentrated in vacuo to give a yellow solid. This was purified by column chromatography, loading in dichloromethane onto a silica cartridge 50 g, using a 0-100% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (680 mg).