Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].[N+](C1C=CC(S(O)(=O)=O)=CC=1)([O-])=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][S:25]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=1)(=[O:26])=[O:27])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A solution of (±)-trans-2-azido-cyclopentanol (1.27 g, 10.0 mmol) (Zhang, Z. da; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602) in CH2Cl2 (14 mL) at 0° C. was treated successively with pyridine (0.88 mL, 10.9 mmol) and 4-nitro-benzenesulfonyl chloride (2.22 g, 10.0 mmol) and allowed to warm to room temperature slowly. The reaction was stirred for 4 d, during which additional pyridine (0.9 mL, 11 mmol) and 4-nitro-benzenesulfonic acid (2.2 g, 10 mmol) was added, and partitioned between CH2Cl2 and 1 N HCl. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with saturated NaHCO3, dried and concentrated. Chromatography of the residue with 10:1–4:1 hexanes:EtOAc gave the product (2.63 g, 84%) as a yellow oil: 1H NMR δ 1.61–1.90 (m, 4H), 2.00–2.16 (m, 2H), 3.96 (m, 1H), 4.72 (m, 1H), 8.14 (m, 2H), 8.43 (m, 2H).
Reaction SMILES: F[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:14]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)c1cccnc1F
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C1CCN(c2ncccc2C(=O)O)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 116.9 %

Procedure:
To a suspension of resin B (1.2 mmol/g, 5.0 g, 8.0 mmol) in pyridine (12 mL) was added dimethyl-pyrrolidin-3-yl-amine (1.37 mL, 12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.2 mL, 14.4 mmol) at room temperature. The mixture was agitated at 100° C. for 12 hours under a nitrogen atmosphere. The resin was washed with DCM then MeOH (3×), and dried under vacuum. Compound C was cleaved off the resin with the addition of 50% trifluoroacetic acid in DCM. The mixture was agitated at room temperature for 30 minutes. The resin was washed with DCM (3×), and the filtrate was concentrated using a rotary evaporator. 1 N HCl aqueous solution (2 mL) was added and then lyophilized to yield compound C as a light pink gum (2.2 g). The compound was taken onto the next step without further purification. 1H-NMR δ (CDCl3): 10.85 (s, 1H), 8.26 (dd, 1H, J=4.8 Hz, J=1.6 Hz), 7.96 (dd, 1H, J=7.2 Hz, J=2.0 Hz), 6.81 (dd, 1H, J=7.6 Hz, J=4.8 Hz), 3.92-3.94 (m, 1H), 3.70-3.80 (m, 2H), 3.52-3.54 (m, 1H), 3.43 (m, 1H), 2.80 (m, 6H), 2.20 (m, 1H), 2.17 (m, 1H). ESMS: 236.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]#[CH:16].N1C(C)=CC=CC=1C>CN(C)C(=O)C>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:16][C:15]#[CH:14])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: C#CCBr
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: C#CCNc1ccc(S(=O)(=O)N(C)C)cc1
Yield: 602.3 %

Procedure:
Under an atmosphere of nitrogen gas, a mixture of 17 g (0.0085 mol) of 4-amino-N,N-dimethylbenzenesulfonamide, 25.5 ml (0.229 mol) of propargyl bromide, and 20.4 ml (0.175 mol) of 2,6-lutidine in 250 ml of N,N-dimethylacetamide is stirred at 90° for three and one-half hours, allowed to cool, and concentrated in vacuo. The concentrate is taken up in dichloromethane and water; the organic layer is separated, washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed over 1.1 kg of silica gel with a gradient of ethyl acetate in toluene of 10 to 15% to give 12.2 g of product, Rf (10% methanol/dichloromethane)≃0.84. Recrystallization from ethanol affords 10.2 g (50%) of product, as off-white crystals; mp 128°-131° C.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[CH3:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[CH3:8][Si:9]([O:10][CH2:11][CH3:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCC/C=C/CO
Agent: CCO[Si](C)(OCC)OCC
Product: CC/C=C\CCO

Procedure:
0.4 Percent of a reaction product formed by reacting a single perfume (trans-2-hexenol) with methyl triethoxysilane in a molar ratio of 2:1, which was used in the foregoing Reference Example, and 0.9 percent of a reaction product formed from cis-3-hexenol and methyl triethoxysilane in a molar ratio of 2:1, were mixed with 98.7 percent of another perfume component to prepare a green apple type blend perfume. A fragrant article was prepared by impregnating the blend perfume into circular filter paper of 65 mm in diameter and 3 mm in thickness. The article was then volatilized at room temperature.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH2:26])=[N:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[C:10](=[O:27])[CH:9]1[CH2:28][CH2:29][CH3:30])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([CH2:15][N:11]3[CH:12]([CH3:14])[CH2:13][NH:8][CH:9]([CH2:28][CH2:29][CH3:30])[C:10]3=[O:27])=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: CCCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)C(C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of 4-[4-amino-quinazolin-7-ylmethyl]-5-methyl-3-oxo-2-propyl-piperazine-1-carboxylic acid tert-butyl-ester (0.91 g, 2.2 mmol) in EtOAc (40 mL) is bubbled HCl (gas) for 5 min. at 0° C. After this time, the solution is stirred at ambient temperatures for 15 min. The solution is concentrated. The residue is purified by column chromatography eluting with 1:5:100 NH4OH/MeOH/CH2Cl2. The title compound (0.5 g) is obtained as a white solid. 1H NMR (300 MHz, CDOD) δ8.40 (s, 1H), 8.04 (d, 1H), 7.52 (s, 1H), 7.36 (m, 1H), 5.10 (d, 1H), 4.45 (d, 1H), 3.55 (m, 2H), 3.10 (m, 1H), 2.81 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H), 1.44 (m, 2H), 1.29 (d, 3H), 0.96 (m, 3H).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5]1([CH:11]=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[CH:5]1([C@H:11]([OH:12])[C@H:2]([CH3:3])[CH:1]=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CC1CCCCC1
Reactant: CCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](C=O)[C@@H](O)C1CCCCC1
Reaction time: 22 h
Yield: 87 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 20 h to a stirring suspension of cyclohexane carboxaldehyde (242 μL, 2.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 22 hours, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 87% yield (148 mg, 0.87 mmol), 99% ee and 93:7 anti: syn. IR (film) 3438, 2928, 2853, 1722, 1450, 1396, 1376, 1314, 1186, 1112, 1063, 975.8, 893.2, 847.5 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.75 (d, 1H, J=2.1 Hz, CHO); 3.53 (dd, 1H, J=7.2, 4.8 Hz, CHOH); 2.58 (m, 1H, CHCH3); 1.8-1.0 (br m, 11H, cyclohexyl); 1.10 (d, 3H, J=7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 206.1, 77.1, 49.2, 40.7, 30.3, 26.73, 26.69, 26.68, 26.4, 11.4; HRMS (CI) exact mass calcd for [M+H]+(C10H19O2) requires m/z 171.1385, found m/z 171.1386. [α]D=−5.1 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the corresponding 4-cyclohexyl-2,2,5-trimethyl-[1,3]dioxane (obtained by NaBH4 reduction followed by acetonide protection of the 1,3-diol according to the method of Goto, in Kitamura et al. (1984) J. Am. Chem. Soc. 106:3252) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S,3R) anti isomer tr=17.8 min, (2R,3R) anti isomer tr=18.7 min, (2R,3R) and (2S,3R) syn isomers tr=21.0, 22.2 min.
Reaction SMILES: C(O)(=O)C.Cl.[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7]1.[CH:13](=O)[C:14]([CH3:16])=[O:15].[Na+].[Cl-]>O>[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][N:12]=[CH:13][C:14](=[O:15])[CH3:16])[CH2:7]1
Reactant: NNC1CCOC1
Reactant: CC(=O)C=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
Acetic acid (1.7 mL) was slowly added to a solution of tetrahydrofuran-3-ylhydrazine hydrochloride (2.50 g, 18.0 mmol) (prepared as described by Bacon, E. R.; Singh, B.; and Lesher, G. Y. in U.S. Pat. No. 5,294,612) in water (30 mL). This mixture was then added dropwise to a solution of pyruvaldehyde (2.59 g, 2.34 mL, 14.4 mmol) in water (240 mL). The mixture was stirred overnight at room temperature. The mixture was poured into a seperatory funnel, NaCl was added and dissolved in the aqueous phase and then extracted with CH2Cl2 (6-times). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide crude material, which was purified by preadsorbing the oil on SiO2 followed by chromatography (Isco, 80 g RediSep column) eluting with a 0-80% EtOAc/heptane gradient over 80 minutes. Analysis of fractions resulted in isolation of 2-oxopropanal tetrahydrofuran-3-ylhydrazone (1.19 g, 53%).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28].CC(C)([O-])C.[Na+].O1CCOCC1>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: COCCNCCOC
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: COCCN(CCOC)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 99.3 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), bis(2-methoxyethyl)amine (0.270 ml, 1.83 mmol), X-phos (17.4 mg, 0.0365 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.0 mg, 0.0120 mmol), sodium tert-butoxide (87.5 mg, 0.912 mmol) and dioxane (4 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (230 mg, 99.1%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([N:41]3[CH2:42][CH2:43][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:39][CH2:40]3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-3-(4-benzyloxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-propionic acid was condensed with 4-phenyl-piperidine hydrochloride to give the title compound, mp=75-78° C.
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.S(Cl)([Cl:15])=O>N1C=CC=CC=1>[Cl:15][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: OCC1COc2ccccc2O1
Solvent: c1ccncc1
Product: ClCC1COc2ccccc2O1

Procedure:
0.42 mole of 2-hydroxymethyl-1,4-benzodioxane, 0.42 mole of thionyl chloride and 600 ml of dry pyridine were heated at 100° C. for 3 hours. After the mixture had been cooled, ice-cold dilute hydrochloric acid was added and the mixture was extracted with ether. After drying, the solvent was removed and the residue was distilled in vacuo. Boiling point: 80° C. (0.9 mbar).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])(=[O:4])[CH3:3].[CH:20](Cl)(Cl)Cl>CO>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:19])=[C:10]([CH:18]=1)[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[O:12])(=[O:4])[CH3:3]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 0 °C

Procedure:
Hydrogen chloride gas was passed through a gently boiling solution of 3-(5-acetamido-2-hydroxybenzoyl) propionic acid (1.2g) in dry methanol (20 ml) until esterification was complete. The reaction mixture was then poured into ice-water and chloroform added. The chloroform extract was washed with sodium bicarbonate solution then water, and finally dried and evaporated to leave methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate as a solid (0.75g, 59%; m.p. 145°-147° C; M+, 265, M 265).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:15].[CH3:16]O>>[ClH:15].[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(-c2ccccc2)n[nH]1

Procedure:
3-Phenyl-1H-pyrazole-5-carboxylic acid (4.96 g) was suspended in methanol (80 mL) and concentrated hydrochloric acid (22.0 mL) and the reaction mixture heated at reflux overnight. Upon cooling the title compound (3.00 g) precipitated from the reaction mixture, was filtered and dried under vacuum. The material was used without further purification having the following physical data.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[O:34]=[C:35]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[H-].[Na+].C(Br)(Br)Br>C(Cl)(Cl)(Cl)Cl.COCCOC.O>[CH2:40]([O:39][C:37](=[O:38])[CH:36]([CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])[CH:6]=1)[C:35]([C:42]1[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=1)=[O:34])[CH3:41]
Reactant: Cc1cccc(OCC(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: BrC(Br)Br
Product: CCOC(=O)C(Cc1cccc(OCC(F)(F)F)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of 3-(2,2,2-trifluoroethoxy)toluene (7.34 g, 38.6 mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide (7.56 g, 42.5 mmol) and 2,2′-azobis(isobutyronitrile) (633 mg, 3.86 mmol) and the mixture was heated under reflux overnight. The insoluble material was filtered using celite and the filtrate was concentrated to prepare a bromo form. To a solution of ethyl 3-oxo-3-(4-fluorophenyl)propionate (7.3 g, 34.7 mmol) in 1,2-dimethoxyethane (70 ml) was added sodium hydride (60% in oil, 1.39 g, 34.7 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of the bromo form synthesized above in 1,2-dimethoxyethane (20 ml) and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from diisopropyl ether-hexane to give ethyl-3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate (4.23 g, 31%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Br[C:26]#[N:27]>C(#N)C>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26]([NH2:27])=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: N#CBr
Solvent: CC#N
Product: CCC(CC)Oc1cc(C)nc2c1nc(N)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with BrCN in acetonitrile at room temperature overnight. The mixture was quenched with water and adjusted to pH 8.0 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give crude material. The material was purified through silica gel column chromatography to give the title compound as a white solid, mp. 159-161° C. 1H NMR(CDCl3) d 7.05(s,2H), 6.5(s,1H), 4.6(m,1H), 4.3(m,2H), 2.45(s,3H), 2.35(s,3H), 2.0(s,6H), 1.7(m,4H), 1.0(t,6H) ppm.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH2:13][CH2:14][CH:15]=2)[N:10]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C2(CCOCC2)C2=CCCC=C21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate from Step B (55.0 mg, 0.173 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0.12 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 25.0 mg (69%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC[C@H]1CN(Cc2ccccc2)CCN1
Solvent: ClCCl
Product: CC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from example 69 part b) (4.74 g) in DCM (150 ml) was added (BOC)2O (5.52 g) and the reaction stirred at RT for 48 h. The reaction was concentrated under reduced pressure. The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent)), to give the sub-titled compound as a colourless oil (6.09 g).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[OH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]=1[NH2:24]>CO.C1(C)C=CC=CC=1>[CH3:1][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([OH:14])[C:16]=1[NH2:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: CO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(O)c1N
Reaction time: 16 h

Procedure:
A solution of (trimethylsilyl)diazomethane in hexane (2.0 M, 10.9 mmol) is added dropwise (10 min) to a mixture of 3-hydroxyanthranilic acid (9.93 mmol) in MeOH (10.5 mL) and toluene (42 mL). The mixture is stirred for 16 h, concentrated in vacuo, diluted with ether and EtOAc and washed several times with water. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by FC (heptane to heptane/EtOAc 7/3) to give the desired ester as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]#[N:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)C(C#N)CCO2
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(CNC(C)=O)CCO2

Procedure:
The nitrile obtained in Step A (200 mg; 1.05 mmol) is solubilised in the reactor of a Parr apparatus in 15 ml of acetic anhydride. Raney nickel (60 mg; 30% by weight) and also sodium acetate (1.5 eq; 1.58 mmol; 130 mg) are added. The reactor is placed under hydrogen pressure of 580 psi at 50° C. for 12 hours. When the reaction is complete, filtration over Celite and then rinsing with AcOEt are carried out. The product is purified by flash chromatography on silica gel (eluant: AcOEt (100%)). The white solid obtained is recrystallised from a pentane-ether mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cc(Cl)cc(Cl)c2)CCCCC1
Reaction time: 0.02 h
Yield: 79.1 %

Procedure:
To a solution of 2-(3,5-dichlorophenyl)acetonitrile (2 g, 10.75 mmol) in N,N-dimethylformamide (40 mL) at 0° C. was added 60% sodium hydride (0.946 g, 23.65 mmol) and the mixture was stirred for 1 min. Then 1,5-dibromopentane (1.464 mL, 10.75 mmol) was added, and the mixture was stirred at 0° C. for 1 hr and at room temperature for 14 hrs. About 100 mL of water was added, and the product was extracted with ethyl acetate. The extract was washed with water and brine. The combined aqueous layers were extracted with ethyl acetate once and washed with brine. The extracts were dried over sodium sulfate and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) by eluting with 5:95 EtOAc-hexane to give the desired 1-(3,5-dichlorophenyl)cyclohexanecarbonitrile (2.16 g, 79% yield) as a crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.38 (2H, d, J=1.76 Hz), 7.32 (1H, t, J=1.76 Hz), 2.14 (2H, d, J=11.86 Hz), 1.67-1.94 (8H, m).