Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: OCC(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A mixture of 2-Hydroxymethyl-1,3-propanediol (9.0 g, 61.6 mmol), 2,2-dimethoxypropane (11.7 ml, 95.2 mmol) 4-toluenesulphonic acid monohydrate (0.49 g, 2.58 mmol) and tetrahydrofuran (450 ml) was stirred at 20° C. for 1 hour. Triethylamine (5 ml) was then added and the solvent removed under reduced pressure. Chromatography on silica gel (eluted with chloroform ethanol, 10.1) afforded the title compound (9.62 g, 78%) as a colourless oil. 1R: υmax (film) 3431, 2993, 2943, 2874, 1482, 1456, 1373 cm-1. 1H NMR: δH [(CD3)2SO] 1.30(6H, s, 2×CH3), 1.69(1H,m,CH), 3.38(2H,dd, J=5.2, 6.6 Hz, CH2OH), 3.61(2H,dd, J=11.8, 7.1 Hz, 2×H(ax)), 3.82 (2H, dd, J=11.8, 4.4 Hz, 2×H(eq)), 4.53(1H, t, J=5.2 Hz, D2O exchangable, OH). Found: C, 56.73; H, 9.80%. C7H14O3.0.01H2O requires: C, 56.80; H, 9.69%.
Reaction SMILES: [CH3:1][C:2]1([C:23]#[C:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:7][CH2:6][C:5]2[C:8]([CH3:22])=[C:9]([O:14]CC3C=CC=CC=3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1>[Ni].C(O)C.C(OCC)(=O)C>[CH3:13][C:10]1[C:11]([CH3:12])=[C:4]2[C:5]([CH2:6][CH2:7][C@:2]([CH2:23][CH2:24][CH2:25][C@@H:26]([CH2:27][CH2:28][CH2:29][C@@H:30]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:37])[CH3:38])([CH3:1])[O:3]2)=[C:8]([CH3:22])[C:9]=1[OH:14]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C#CCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 6 h
Yield: 101.2 %

Procedure:
A mixture of [2S-(4R*,8R*,)]-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-1-tridecynyl)-6-(phenylmethoxy)-2H-1-benzopyran, (200 mg, 0.39 mmol) and 40 mg of Raney Nickel in 5 mL of ethanol and 5 mL of ethyl acetate was hydrogenated at 25° C. and atmospheric pressure for 6 h. Workup in the usual manner and purification of the crude product by chromatography on silica gel (eluent 1:5 ether-hexanes) gave 170 mg of (2R,4'R,8'R)-α-tocopherol as a pale yellow oil, identical in all respects with a known sample.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br.O>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:27])=[C:19]([F:18])[CH:20]=2)[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccs2)c[nH]1
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-I) in dry dimethylformamide, cesium carbonate was added at 40-50° C. To this was added 3,4-difluro benzyl bromide and stirred overnight at 40-50° C. Reaction mixture was taken in to water and extracted with ethyl acetate, organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-II).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:19]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:50])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=3)[S:33][C:32]=2[CH:51]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[C:19]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:18][CH:17]=3)=[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:50])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:38][CH:37]=3)[S:33][C:32]=2[CH:51]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Oc1ccc(-c2cc3ccc(OC(=O)c4ccccc4)cc3s2)cc1)c1ccccc1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1)c1ccccc1

Procedure:
An acid chloride was formed from 18.1 g. of 4-(2-pyrrolidinoethoxy)benzoic acid, hydrochloride, as described in Example 1. The acid chloride was used to acylate 20 g. of 6-benzoyloxy-2-(4-benzoyloxyphenyl)benzo[b]thiophene as described above in Example 1, using 53.2 g. of aluminum chloride. A sample of the impure product, a tan foam, was recrystallized from denatured ethanol to obtain an analytical sample, m.p. 218°-222°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1cc(F)ccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc(F)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.0 g, 3.2 mmol) in dry DMF (25 mL) was reacted with methyl 2-chloro-5-fluorobenzoate (1.22 g, 6.4 mmol) in the presence of NaH (50%, 0.776 g, 16 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:26]#[N:27]>ClCCl>[CH3:32][O:31][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C#N)cc1O
Reactant: OCCCN1CCOCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C#N)cc1OCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g 3-Morpholine-4-yl-propan-1-ol was dissolved in dichloromethane, cooled to 0° C., 3.25 mL methanesulfonylchloride was added and the mixture was stirred for 2 h at ambient temperature. Then 7 g potassium carbonate and 3-hydroxy-4-methoxybenzonitrile were added and the reaction was stirred at 45° C. for 3 h. The mixture was concentrated and 70 mL dimethylacetamide was added and stirred at 120° C. for 3 h. After this time, the mixture was diluted with dichloromethane and extracted with water, the organic phase was dried over magnesium sulfate and concentrated.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:31][CH2:30]1>>[CH:29]1([C:32]2[N:33]=[CH:34][C:35]([C:2]3[C:3]([N:22]4[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]4)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]4[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=4)=[O:8])[CH:21]=3)=[CH:36][CH:37]=2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. UPLC-MS (condition 1) tR=2.30 min, m/z=499.0 [M+H]+, m/z=497.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.04 (m, 4H) 1.49-1.62 (m, 1H) 1.77-1.88 (m, 1H) 2.10-2.19 (m, 1H) 2.18-2.26 (m, 1H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.09-3.20 (m, 2H) 3.21-3.29 (m, 1H) 3.29-3.41 (m, 2H) 4.60 (br. s, 1H) 7.29-7.40 (m, 3H) 7.64 (dd, J=8.07, 2.20 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.99 (d, J=2.20 Hz, 1H) 8.45 (d, J=2.20 Hz, 1H) 8.73 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:14]=2[C:15]([O:17]CC)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:14]=2[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)O)cc1OC
Yield: 75 %

Procedure:
30% strength sodium hydroxide (2 ml) is added to a solution of ethyl 2-(3,4-dimethoxyphenyl)-6-phenylnicotinate (compound no. 309; 3.6 g; 0.01 mole) in 95% strength alcohol (100 ml). The reaction medium is heated for 2 h to 60°-70° C. The medium is concentrated under reduced pressure and the residue is dissolved in water (100 ml). The medium is acidified with concentrated hydrochloric acid (2 ml): a gum is released. The mixture is extracted with ethyl acetate (100 ml). The solution is washed with water (2×100 ml), dried over anhydrous magnesium sulphate and then concentrated under reduced pressure. A foam is obtained which is crystallized by trituration in ether (50 ml). After filtration and drying, a beige powder (2.5 g; yield=75%) is obtained, m.p. 178° C. Working in the same manner, the compounds of formula (IV"') in which Z3 is the hydroxyl group and R371 has the meanings indicated below, is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16]CCCC(C)(C#N)C)[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40]Br)#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([CH3:43])([C:34]#[N:35])[CH3:42])[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)CCCCBr
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCC(C)(C)C#N
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N

Procedure:
1-(Benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene was prepared as described in Example 1 for the synthesis of 1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(5-methyl-5-cyanohexyl)oxy]-benzene substituting 6-cyano-6-methyl-1-bromoheptane for 5-cyano-5-methyl1-bromohexane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH:14]12[O:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]2.Cl>CN(C)C=O>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]3[OH:20])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: C1CCC2OC2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@@H]1CCCC[C@H]1n1cnc2cc(Cl)c(Cl)cc21
Yield: 88 %

Procedure:
5,6-Dichlorobenzimidazole (Townsend and Revankar, Chem. Rev. 1970, 70:389, and references cited therein) (5.00 g, 26.0 mmol) was dissolved in N,N-dimethylformamide (65 ml) and sodium hydride (60% oil dispersion, 50 mg) was added. The solution was heated to 145° and cyclohexene oxide (Aldrich, 7.8 g, 26 mmol) was added in 3 portions over 3 hours. The solution was neutralized with 1 N hydrochloric acid, and evaporated to a purple solid. The solid was recrystallized from ethanol to give title compound as pink crystals (12.55 g, 88%); m.p. 236-238° C.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[Cl-].[Na+].[CH2:15](O)[CH3:16]>>[CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:15][CH3:16])=[O:4]
Reactant: CC[C@H](C)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)CC
Temperature: 25 °C
Yield: 822.7 %

Procedure:
9 g (88 mmol) of the (S)-(+)-2-methylbutyric acid obtained by the method of the above Referential Example 1 was mixed with 20.24 g of 99.5% by vol. ethanol containing 0.4 g of conc. sulfuric acid and heated under reflux for 4 hours. After the completion of the reaction, the mixture was cooled to room temperature and poured into 150 ml of a saturated aqueous solution of sodium chloride. The oily layer was extracted with n-hexane and thus separated from the aqueous layer. Then it was further washed with a saturated aqueous solution of sodium chloride twice and dehydrated over calcium chloride. After distilling off the n-hexane under atmospheric pressure, the temperature was further elevated. Thus 9.3 g of (S)-(+)-ethyl 2-methylbutyrate (boiling point: 135° C./760 mmHg) was obtained (yield: 81.3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.CCCCCC>[C:12]([N:15]1[CH2:20][CH2:19][C:18]2([CH2:10][C:9](=[O:11])[C:3]3[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=3[O:21]2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)N1CCC2(CC1)CC(=O)c1c(O)cccc1O2

Procedure:
2',5'-Dihydroxyacetophenone and 1-acetyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a yellow solid, m.p. 114°-116° C. (from EtOAc/hexane).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+].[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:2]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCC#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC#CC(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
A mixture of 16.5 g of 1-bromo-2-nonadecyne in 50 ml of ethanol is added to 3.0 g of 60% sodium hydride and 11.4 ml of diethyl malonate in 100 ml of ethanol. This mixture is stirred one hour and then evaporated. The residue is washed with ether, twice with dilute hydrochloric acid and brine. The residue is then purified by flash chromatography, (5% ethyl acetate:petroleum ether), to give 12.1 g of the desired compound as white needles, mp. 33°-34° C.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][CH3:28])=[C:13]([C:15]2[NH:16][C:17](=[O:25])[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:14]=1>>[CH2:27]([O:26][C:12]1[CH:11]=[CH:10][C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:25])[C:18]2[N:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:28]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Product: CCOc1ccc(NS(=O)(=O)C(C)C)cc1-c1nc2cccnc2c(=O)[nH]1

Procedure:
The title compound was prepared using 2-propylsulphonyl chloride and 2-(5-amino-2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Example 20), following the procedure of Example 12, and was obtained as a hydrated solid (59%), m.p. 211-213° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[ClH:3].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:31]([CH:27]1[CH2:30][CH2:29][CH2:28]1)=[O:32]
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and cyclobutanecarboxylic acid chloride as the starting materials in 40% yield. LCMS for C23H23ClN5O (M+H)+: m/z=420.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.CC[N:45]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C)C=O>[C:39]([CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:25]2[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:24]=2[CH:11]2[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12]2)[CH2:33][CH2:34]1)(=[O:40])[NH2:45]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 80 °C

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(1-hydroxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.069 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added EDCI (26.5 mg, 0.139 mmol), HOBT (18.8 mg, 0.139 mmol), diisopropylethylamine (35.9 mg, 0.278 mmol), NH4Cl (7.4 mg, 0.278 mmol). The reaction mixture was heated at 80° C. for 1 h, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc=8:92) to give racemic(2′R, 3R, 4′S)-2′-[2-(1-carbamoylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 25.6 mg, 51%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,5-difluorophenyl)-propionic acid (8.0 g, 27 mmol) in anhydrous dichloromethane (200 mL) at 0° C. is added N-ethyl-N′,N′-dimethylaminoethyl carbodiimide (5.09 g, 27 mmol), followed by 4-nitrophenol (4.4 g, 32 mmol). After stirring for 30 min, the solution is washed sequentially with saturated NaHCO3 (aq), water, 1.0 M citric acid (aq), water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a slightly red solid (8.11 g, 19 mmol), contaminated with residual 4-nitrophenol, which may be used without purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:39]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:39][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)ccc5ccc2c3c54)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(Br)c5ccc2c3c54)c2ccccc12
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixed solution of 1.7 g of 1,6-di(4-methylnaphthalen-1-yl)pyrene, 0.54 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 6 hours. The solution was cooled to room temperature and 50 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The resulting concentrate was recrystallized from toluene and then vacuum-dried at 70° C. to obtain 1.5 g of 1-bromo-3,8-di(4-methylnaphthalen-1-yl)pyrene as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].FC(F)(F)C(O)=O>ClCCl>[N:28]([C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:15]2[C:13]3[N:14]=[C:9]([NH:8][C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)[N:10]=[CH:11][C:12]=3[N:17]=[N:16]2)=[CH:19][CH:20]=1)([CH3:26])[CH3:25])=[N+:29]=[N-:30]
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)N=[N+]=[N-])cc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (237 mg, 0.65 mmol) and sodium azide (186 mg, 2.86 mmol) in dichloromethane (2.5 ml) is added dropwise under external cooling a solution of trifluoroacetic acid (822 μl, 10.7 mmol) in dichloromethane (2.5 ml). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between dichloromethane and diluted aqueous ammonia. The organic phase is dried over sodium sulfate and evaporated to afford {3-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine as yellow-green powder; HPLC/MS 2.01 min (A), [M+H] 390.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18](Cl)([F:20])[F:19])=O)(C)(C)C.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C:18]([F:19])([F:20])[O:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:31])[F:32])=[CH:25][CH:26]=3)=[N:10][C:11]=2[CH:16]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)n1c(C(F)(F)Cl)nc2cc(Br)ccc21
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(OC(F)(F)c2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-(chloro-difluoro-methyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (1.00 g, 2.62 mmol), 4-trifluoromethyl-phenol (0.42 g, 3.93 mmol), and N,N-diisopropylethylamine (0.6 mL, 3.44 mmol) was heated to 85° C. for 14 hours. The crude product was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a yellow oil (0.58 g, 54%).