Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:30])=[CH:13][C:14]4[CH2:15][CH2:16][C@@H:17]5[C@@H:26]([C:27]=4[CH:28]=3)[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]5[CH2:19][CH2:20][C:21]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)C.[BH4-].[Na+]>CO>[C:1]12([C:11]3[C:12]([OH:30])=[CH:13][C:14]4[CH2:15][CH2:16][C@@H:17]5[C@@H:26]([C:27]=4[CH:28]=3)[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]5[CH2:19][CH2:20][C@@H:21]3[OH:29])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 59.5 %

Procedure:
2-(1-Adamantyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (250 mg, 0.62 mmol) was added to cold ethanol (25 mL) and methanol (10 mL) to give a turbid solution. Sodium borohydride (NaBH4, 140 mg) was added in one portion and the reaction was continued with stirring for 2 hours. Solvents were removed on a rotary evaporator and crushed ice was added. On standing overnight, the initially formed oil became a solid. The solid was filtered and washed with water until the filtrate was pH neutral. The solid was dried in a vacuum oven at 50° C. to give the crude product (0.25 g), which was purified by flash chromatography (silica gel eluted with 18% ethyl acetate in hexanes). The pure product (200 mg, 79.6%) was recrystallized from chloroform and hexanes to obtain crystals (150 mg), and was then characterized as follows: (i) melting point=174-175° C.; (ii) 1H NMR (CDCl3, 300 MHZ) δ0.81 (s, 3H, C18—CH3), 2.76 (m, 2H, C6—CH2), 3.73 (t, 1H, C17—H), 4.78 (s, 1H, C3—OH), 6.38 (s, 1H, C4—H), 7.16 (s, 1H, C1—H); (iii) 13C NMR (CDCl3, 300 MHZ) 60.95, 23.02, 26.33, 27.12, 28.77, 28.98 (3×C), 30.49, 36.54, 36.71, 37.01 (3×C), 38.89, 40.68 (3×C), 43.20, 44.22, 49.96, 81.99, 116.84, 124.06, 132.06, 133.83, 135.20, 152.36.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH:15]=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH:17]=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>C(#N)C>[CH:8]1[C:7]2[C:12](=[C:13]([CH:15]=[O:16])[C:14]3[C:5]([C:6]=2[CH:17]=[O:18])=[CH:4][CH:3]=[CH:2][CH:1]=3)[CH:11]=[CH:10][CH:9]=1
Reactant: O=CC1c2ccccc2C(C=O)c2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1c2ccccc2c(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 240 mg. of the product of Example 2 (prepared as described) in 15 ml. of acetonitrile is added a solution of 0.30 ml. of triethylamine in 5 ml. of acetonitrile. The reaction mixture is stirred at room temperature for 4 hours then is cooled in an ice bath. The precipitate is collected by filtration to give 136 mg. of the desired crude product as orange crystals, mp. 224°-228° C.
Reaction SMILES: [CH2:1]([O:3][S:4]([O-:7])(=O)=[O:5])[CH3:2].[NH+]1C=CC=CC=1.[Cl-:14].OCC[N+]1C=CC=CC=1>N1C=CC=CC=1>[CH2:2]([Cl:14])[CH2:1][OH:3].[Cl:14][S:4]([OH:7])(=[O:5])=[O:3]
Reactant: [Cl-]
Reactant: CCOS(=O)(=O)[O-]
Agent: OCC[n+]1ccccc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: O=S(=O)(O)Cl
Product: OCCCl

Procedure:
German Published Application DAS 1,191,652 states that, for example, pyridinium ethylsulfate (2-pyridinium-1-sulfatoethane) can be prepared in an expensive procedure by reacting hydroxyethylpyridinium chloride, obtained from pyridine and ethylenechlorohydrin, with chlorosulfonic acid. In this procedure too, the yield and purity are unsatisfactory.
Reaction SMILES: COCCOCCO.C(Cl)(Cl)=O.[NH2:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]([NH:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:30]
Reactant: COCCOCCOC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COCCOCCO
Product: COCCOCCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.8 ml (168 mmol) of diethylene glycol monomethyl ether are added dropwise at 0° to 100 ml of a 20% solution of phosgene in toluene and the mixture is stirred overnight at RT. Excess phosgene is expelled with nitrogen and the reaction solution is washed with water and concentrated by evaporation. Analogously to Example 1c, 10 g (85.4 mmol) of (L)-valine are added to the crude 2-(2-methoxyethoxy)ethylchloroformate (15.6 g, 85.4 mmol) yielding the title compound in the form of a colourless resin. 1H-NMR (200 MHz, CD3OD): 4.18 (m, 2H), 4.05 d, J=6 Hz, 1H), 3.72-3.40 (m, 8H), 3.35 (s, 3H), 2.18 (m, 1H), 0.95 (t, J=7H, 6H).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:8]=1[CH3:28])C.Cl.[NH:33]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[NH2:34].O>CO>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([NH:33][N:34]=[CH:4][C:5]#[C:6][C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)[C:8]=2[CH3:28])=[CH:36][CH:37]=1)#[N:40]
Reactant: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(C#CC=NNc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In a 100 mL round-bottomed flask, methyl 6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM2, 1.136 g, 2.59 mmol) and 4-hydrazinylbenzonitrile hydrochloride (0.508 g, 3.00 mmol) were stirred in methanol (25 mL) and water (2.5 ml) under air at 65° C. After 1 h, the mixture was allowed to cool to 45° C., water (50 ml) was added and the mixture then cooled to RT. After stirring for 30 minutes, the solid was filtered off, washed with water (100 ml) and then air dried to give methyl 6-(3-(2-(4-cyanophenyl)hydrazono)prop-1-ynyl)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (1.18 g, 95%) as a yellow solid.
Reaction SMILES: Cl[CH:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[CH:8]1([CH:2]([C:19]2[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[C:15]([F:14])[CH:20]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert.butylate were dissolved in 70 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 ml) was carefully added dropwise and stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EtOAc (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EtOAc in cyclohexane) and produced 5.5 g (49%) of product.
Reaction SMILES: N[C:2]1[CH:7]=CC(OC)=[CH:4][C:3]=1S(N)(=O)=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]>>[O:24]=[S:23]1(=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=2[N:14]2[CH2:7][CH2:2][CH2:3][CH:4]2[NH:26]1
Reactant: COc1ccc(S(N)(=O)=O)c(N)c1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Product: O=S1(=O)NC2CCCN2c2cc(O)ccc21

Procedure:
In Step A, 2-amino-5-methoxybenzenesulphonamide is replaced by 2-amino-4-methoxybenzenesulphonamide.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10](=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)no1
Solvent: c1ccncc1
Product: Clc1nc(-c2ccccc2)no1
Temperature: 100 °C
Reaction time: 6 h
Yield: 52.7 %

Procedure:
To a mixed solution of 3-phenyl-1,2,4-oxadiazol-5(4H)-one (2.00 g, 12.3 mmol) in phosphorus oxychloride (36 g) was added pyridine (1.93 ml, 23.9 mmol), and the mixture was stirred at 100° C. for 6 hours. The solvent was distilled off under reduced pressure. The residue was poured to ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.17 g (52.4%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16](=O)[NH2:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(N)=O)CC1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC#N)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of trans (4-carbamoylmethoxy-cyclohexyl)-carbamic acid tert-butyl ester (500 mg, 1.80 mmol) and triethylamine (510 μL, 3.70 mmol) in DCM (9 mL) at 0° C. was treated dropwise with a solution of 2,2,2-trichloroacetyl chloride (310 μL, 2.80 mmol) in DCM (1 mL). After the addition the mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was diluted with water and the phases separated. The aqueous phase was extracted with DCM (2×) and the combined organic phases washed with a 10% citric acid solution, a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0-40% ethyl acetate in cyclohexane) to afford 280 mg (60%) of trans (4-cyanomethoxy-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method Q, ESI): RT=3.53 min, m+H=255.0; 1H NMR (400 MHz, CDCl3) δ: 4.37 (s, 1H), 4.27 (s, 2H), 3.47 (m, 1H), 2.05 (d, 4H), 1.44 (s, 9H), 1.38 (m, 2H), 1.18 (m, 2H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: OCc1ccccc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Temperature: 10 °C
Yield: 42 %

Procedure:
L-Mandelic acid (10 g.), 6.91 g. of benzyl alcohol, and 75 mg. of p-toluenesulfonic acid in 70 ml. of benzene was refluxed under a Dean-Stark trap for a total of 28 hours on 4 consecutive days. The crude benzyl ester was obtained by successively concentrating the liquor and cooling it to about 10° C. a number of times. The fractions melting between 97° C. and 105° C. were combined, dissolved in CHCl3 and washed twice with 15 ml. portions of 5% aqueous NaHCO3 solution. After evaporation of the CHCl3, the product was recrystallized from benzene to give benzyl L-mandelate, m.p. 104°-106° C., yield 42%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:12](=[CH2:22])[O:11][C@H:10]1[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][C:24]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][CH2:32][O:33][P:34]([O:38][CH2:39][CH3:40])([CH2:36][OH:37])=[O:35].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClC(Cl)C>[CH2:32]([O:33][P:34]([CH2:36][O:37][C@:12]1([CH3:22])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C@H:10]([N:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][C:24]2=[O:30])[O:11]1)(=[O:35])[O:38][CH2:39][CH3:40])[CH3:31]
Reactant: CCOP(=O)(CO)OCC
Reactant: C=C1O[C@@H](n2ccc(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Temperature: 60 °C
Yield: 25.1 %

Procedure:
To a solution of compound 30.3 (840 mg, 1.85 mmol) in dichloroethane (20 mL) was added diethyl (hydroxymethyl) phosphonate (0.41 mL, 2.87 mmol) and pyridinium p-toluene sulfonate (0.23 g, 0.92 mmol). The mixture was heated to 60° C. for 1 h and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 30.4 (289 mg, 24% yield). 1H NMR (300 MHz, CDCl3): δ0.04 (s, 3H), 0.08 (s, 3H), 0.10 (s, 6H), 0.89 (s, 9H), 0.92 (s, 9H), 1.38 (m, 6H), 1.49 (s, 3H), 3.93 (m, 1H), 4.14 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 5.83 (d, 1H, J=7.7), 6.08 (d, 1H, J=4.0), 7.99 (d, 1H, J=7.3). LRMS (ESI) MH+ C26H52N3O8PSi2 requires 622.9. Found 622.1.
Reaction SMILES: N[C:2]1[C:3]([C:12]2[N:13]=[C:14]([CH2:26][CH3:27])[C:15]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:16][C:17]=2[CH2:18][CH3:19])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[ClH:28].N([O-])=O.[Na+]>O.Cl[Cu]>[Cl:28][C:2]1[C:3]([C:12]2[N:13]=[C:14]([CH2:26][CH3:27])[C:15]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:16][C:17]=2[CH2:18][CH3:19])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CCc1nc(-c2cc3c(cc2N)CCCC3)c(CC)nc1NC(CC)CC
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(-c2cc3c(cc2Cl)CCCC3)c(CC)nc1NC(CC)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 5-(3-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (118 mg, 0.32 mmol), con. HCl (3.41 mL) and cooled with an ice bath for 30 minutes. The solution was yellow. A cold solution of NaNO2 (22.4 mg, 0.325 mmol) in H2O (0.64 mL) was added and the mixture stirred at 0° C. for 30 minutes. A light precipitate was observed. A cold CuCl (38.2 mg, 0.386 mmol) solution in con. HCl (0.853 mL) was added and the mixture continued to stir at 0° C. for 20 minutes. The reaction turned dark. The cooling bath was removed, and after stirring at ambient temperature for 2 hours the color lightened and gas evolution was observed. The reaction was then heated to 60° C. for 20 minutes. More gas evolution was observed. After heating the reaction became clumpy. It was cooled with an ice bath and basified with aq. NaOH. The reaction turned blue/green in color. The now basic reaction mixture was diluted with water, extracted three times with CH2Cl2, the organics were combined, dried with Na2SO4, filtered and concentrated to 110 mg of a crude brown oil. PREP TLC followed by silica gel chromatography (4.5 g) using toluene) gave 4.45 mg (4%) of 5-(3-chloro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine as a yellow oil. Rf 0.16 (toluene). OAMS supporting ions at: ESI+386.1. HRMS (ESI) calcd for C23H32N3CL+H1 386.2363, found 386.2358.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=O)C1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CO.O>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:22]2[CH2:21][N:19]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:24][CH:23]=2)=[CH:2]1.[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:23]2[CH2:22][CH2:21][N:19]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:24]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C=C(c2c[nH]c3ncccc23)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)C1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 7-azaindole (2.6 g, 22.0 mmol) in MeOH (120 mL) and water (60 mL) was added KOH (12.35 g) and the mixture was heated to 75° C. N-Boc-piperidin-3-one (20.4 g, 110 mmol) in methanol was added dropwise and following completion of the addition the mixture was stirred at 75° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was taken up in water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated to dryness. The residue was purified by column chromatography (DCM/MeOH) to afford tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g) and tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (1 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C([BH3-])#N.[Na+]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:23])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]4[CH:32]=[CH:31][C:28]5[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=5[N:34]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc([N+](=O)[O-])cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc([N+](=O)[O-])cc54)CC3)nc2N1
Yield: 7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-nitro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 81), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 7% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17]CC=C)=[CH:9][CH:8]=1)[CH3:2].C(O[C:28](=O)[CH:29](OCC)[CH2:30]C1C2C(=CC=CC=2)C(O)=CC=1)C.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:30][CH:29]=[CH2:28])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Reactant: C=CCOc1ccc(CC(OCC)C(=O)OCC)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Temperature: 160 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
0.87 g (2.65 mmol) [rac]-3-(4-allyloxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester [prepared from [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester (example 150 a] and allylbromide, potassium carbonate in acetone at 60° C.] was stirred for 2 hours at 160° C. without any solvent. The dark residue was purified by flash chromatography (silica gel, hexane/AcOEt=4:1) to yield 0.82 g (94%) of [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[F:13][C:14]([F:42])([F:41])[O:15][C:16]1[CH:17]=[C:18]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[N:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:19]=[CH:20][CH:21]=1>CCOCC>[CH3:29][C:26]([S:24]([NH:23][C:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:38])[F:39])[CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:42])[F:41])[CH:17]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:25])([CH3:27])[CH3:28]
Reactant: Cc1ccccn1
Reactant: CC(C)(C)[S@@](=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC(Cc1ccccn1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
2-Picoline (0.20 mL, 2.0 mmol) was stirred in anhydrous Et2O (20 mL) at 0° C. under Argon. nBuLi (2.5 M in hexanes, 0.84 mL, mmol) was added dropwise. The reaction mixture turned to dark brown, and stirred at 0° C. for 20 min, then at room temperature for 1 h. It was cooled back to 0° C., and (R)—N-(bis(3-(trifluoromethoxy)phenyl)-methylene)-2-methylpropane-2-sulfinamide (prepared as described in Example 82, Procedure 11) (0.906 g, 2.0 mmol) in Et2O (4.0 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h. then at room temperature for 1 h. The reaction was quenched by addition of sat'd NH4Cl. EtOAc was added; the organic layer was washed with H2O and brine, dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%) to give 2-methyl-N-(2-(pyridin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)-ethyl)propane-2-sulfinamide as light tan solids (0.19 g with recovery of 0.59 g of starting material, yield: 48% based on recovery of the starting material). LC-MS (ESI) 547.38 (M+H), retention time=3.90 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 8.36-8.44 (m, 1H), 7.90 (m, 1H), 7.51 (d, J=8.59 Hz, 1H), 7.37 (td, J=7.83, 2.27 Hz, 2H), 7.19-7.24 (m, 2H), 7.11-7.17 (m, 3H), 6.98-7.07 (m, 2H), 6.75 (d, J=7.83 Hz, 1H), 4.15 (d, J=13.90 Hz, 1H), 3.81 (d, J=13.90 Hz, 1H), 1.25-1.33 (m, 9H)
Reaction SMILES: [Br:1]C1(Br)NC(=O)NC1=O.[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH3:21].CC(N=NC(C#N)(C)C)(C#N)C.CC(=O)OCC>ClC1C=CC=CC=1>[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH2:21][Br:1]
Reactant: O=C1NC(=O)C(Br)(Br)N1
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reaction time: 1 h

Procedure:
A mixture of dibromohydantoin (70 g, 0.24 mol) and AlBN (5 g) was added in portions at 150° C. to 2,6-dichloro-3-nitrotoluene (100 g, 0.48 mol) in chlorobenzene (400 ml). After 1 h, a mixture of dibromohydantoin (35 g, 0.12 mol) and AIBN (2.5 g) was again added. After a further 1.5 h, the mixture was allowed to cool and EA (500 ml) was added. This mixture was washed once each with saturated Na2SO3, Na2CO3 and NaCl solution, dried (MgSO4) and concentrated, the title compound being obtained as an amorphous powder.
Reaction SMILES: I[CH:2]1[CH:8]2[CH2:9][CH:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[CH:5]12[CH2:9][CH:8]([O:7][C:6]1=[O:10])[CH:2]=[CH:3][CH2:4]2
Reactant: O=C1OC2CC1CCC2I
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: O=C1OC2C=CCC1C2
Yield: 66.1 %

Procedure:
To 4-iodo-6-oxabicyclo[3.2.1]octan-7-one (8.00 g, 31.7 mmol) in benzene (100 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (7.9 g, 32 mmol) under nitrogen, and the mixture was heated under reflux for 6 h. The white precipitate was filtered off from the cooled solution and washed with ether (100 ml). The combined filtrates were washed with water (50 ml), 1N HCl (50 ml), and brine (25 ml), and then dried over magnesium sulfate. The solvents were removed by rotary evaporation to afford the alkene as a light brown oil (2.6 g, 66%).