Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=4[F:30])=[C:11]3[CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (22.00 g, 86.18 mmol) cesium carbonate (28.08 g, 86.18 mmol), 1,2-difluoro-4-nitrobenzene (13.71 g, 86.18 mmol) and DMA (100 mL) was heated to 100° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between DCM (500 mL) and water (500 mL). The phases were separated, and the organic phase washed with water (3×200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was triturated with diethyl ether (100 mL) and hexanes (200 mL) co-solvent, and the resulting beige powder was filtered. A second crop was obtained after cooling in a −10° C. freezer overnight. The two crops were combined (28 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.16 (m, 2H), 7.86 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 6.48 (d, J=5.5 Hz, 1H), 5.65 (s, 2H), 3.76 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −124.2 (m).
Reaction SMILES: [C:1]([CH:4]([C:38](=O)[CH3:39])[CH:5]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)[CH:6]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:18])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[C:1]([C:4]1[CH:5]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:17](=[O:18])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[C:38]=1[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)C(C(C)=O)C(c1ccc(C#N)cc1)C(C(=O)Nc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)C(C(=O)OCc2ccccc2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of benzyl 4-acetyl-3-(4-cyanophenyl)-5-oxo-2-({[3-(trifluoromethyl)phenyl]amino}carbonyl)hexanoate (7.5 g, 15.6 mmol) (Example 5A), anhydrous magnesium sulfate (15 g, 125 mmol) and Amberlyst 15® (7.5 g) in ethanol (300 ml) is stirred overnight at reflux. The reaction is cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)=O.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O.O>ClCCCl>[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)#[N:1]
Reactant: CCCOc1ccc(CN2CCC(C(N)=O)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCOc1ccc(CN2CCC(C#N)CC2)cc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 27.0 grams (0.10 mole) of 4-aminocarbonyl-N-(4-propoxyphenylmethyl)piperidine in 200 mL of 1,2-dichloroethane was stirred at ambient temperature, and 8.0 grams (0.14 mole) of sodium chloride, followed by 9.2 grams (0.06 mole) of phosphorous oxychloride were added. The reaction mixture was then warmed to reflux, where it stirred for about 1.75 hours. The reaction mixture was cooled to ambient temperature and about 350 mL of water was added. The aqueous layer was separated, washed with two portions of diethyl ether, and then made basic with aqueous 5% sodium hydroxide. The mixture was extracted with two portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and poured through a pad of silica gel. The silica gel pad was washed with 1000 mL of diethyl ether. The combined eluants were concentrated under reduced pressure, yielding 14.5 grams of 4-cyano-N-(4-propoxyphenylmethyl)piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[C:14]([SH:19])=[N:15][CH:16]=[CH:17][CH:18]=1>>[CH3:12][C:13]1[C:14]([S:19][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[Cl:1])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1cccnc1S
Product: Cc1cccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Yield: 50 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 3-methyl-2-pyridinethiol to give 2-chloro-4-nitrophenyl 3-methylpyrid-2-yl sulphide in 50% yield.
Reaction SMILES: [CH3:1][Si:2]([N:5]([CH2:10][CH2:11][CH2:12][Si:13]([CH3:16])(C)Cl)[Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].O1C[CH2:20][CH2:19][CH2:18]1.C([Mg]Cl)=C>>[CH3:1][Si:2]([N:5]([CH2:10][CH2:11][CH2:12][SiH2:13][CH:16]=[C:19]([CH3:20])[CH3:18])[Si:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C[Si](C)(Cl)CCCN([Si](C)(C)C)[Si](C)(C)C
Agent: C=C[Mg]Cl
Product: CC(C)=C[SiH2]CCCN([Si](C)(C)C)[Si](C)(C)C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 53.3 g (0.18 mol) of bistrimethylsilylaminopropyldimethylchlorosilane. To the flask, 160 mL (0.22 mol) of a tetrahydrofuran solution of 1.4M vinylmagnesium chloride was added dropwise over 2 hours at an internal temperature of 60-70° C. Stirring was continued for 4 hours at the temperature. A salt formed was removed by filtration. By subsequent distillation, 40.7 g of a fraction having a boiling point of 94° C./0.4 kPa was collected.
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21]1)=[O:19])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O>[CH2:1]([NH:4][C@@H:17]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:27])[CH3:28])[CH2:21]1)=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN[C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a stirred solution N-allyl-N-{2-[3-(S)-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-2-oxo-1-(S)-phenyl-ethyl}-2-nitro-benzenesulfonamide (8.73 g, 15.6 mmol) in anhydrous dimethylformamide (45 cm3) was added potassium carbonate (6.50 g, 46.8 mmol). The mixture was stirred at ambient temperature for 10 minutes and thiophenol (2.25 cm3, 21.8 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (500 cm3) and extracted with ethyl acetate (3×150 cm3). The combined ethyl acetate extracts were washed with water (2×100 cm3), brine (1×100 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a foul smelling yellow oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:1 to 0:1) to afford the title compound as a yellow viscous oil (5.67 g, 97.1%) with a positive ion ESI (M+H)+375.2.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:10]=1[C:11]([O:13][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoic acid (0.300 g, 0.778 mmol), benzyl 2-hydroxyacetate (0.129 g, 0.778 mmol), EDC (0.448 g, 2.335 mmol) and DMAP (0.048 g, 0.389 mmol) in DCM (30 ml) was stirred at RT overnight. The reaction mixture was washed twice with HCl 1N and then with NaHCO3 5%. The organic phase was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by filtration on silica gel cartridge (petroleum ether:EtOAc=80:20 to 70:30) to give 2-(benzyloxy)-2-oxoethyl 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)benzoate (0.288 g, 0.540 mmol, 69.3% yield, MS/ESI+ 555.96 [MNa]+).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])=[CH:5][CH:4]=1)[CH3:2].[O:17]=[CH:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])O.[Cl-].[NH4+]>CO>[CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C@@H:27]2[O:28][C@H:19]([CH2:18][OH:17])[C@@H:21]([OH:22])[C@H:23]([OH:24])[C@H:25]2[OH:26])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccccc2N)cc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCc1ccc(Cc2ccccc2N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 56 %

Procedure:
2-(4-Ethylbenzyl)aniline 1 (500 mg) was dissolved in methanol (5 ml), and thereto are added D-(+)-glucose 2 (516 mg) and ammonium chloride (25 mg), and the mixture was heated under reflux for 2 hours. Methanol was evaporated under reduced pressure, and water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1-20:1) to give the desired 2-(4-ethylbenzyl)-N-(β-D-glucopyranosyl)aniline 3 (495 mg) as colorless crystals. APCI-Mass m/Z 374 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[N:9]1[CH2:14][CH:13]=[C:12]([O:15][Si](C)(C)C)[CH2:11][CH2:10]1)([O-:3])=[O:2].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:21][CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:9]([C:8]2[NH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10]1
Reactant: C[Si](C)(C)OC1=CCN(c2[nH]ncc2[N+](=O)[O-])CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(c2[nH]ncc2[N+](=O)[O-])CC1F

Procedure:
FIG. 10 shows an exemplary synthesis of 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 52 from 5-chloro-4-nitro-1H-pyrazole 3. Heating 3 with piperidin-4-one hydrochloride hydrate and potassium fluoride in a suitable solvent such as dimethylsulfoxide or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 46. Heating 46 with trimethylsilyl chloride and triethylamine in a suitable solvent such as DMF or using methods described in the literature gives 1-(4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine 47. Fluorination of 47 using SelectFluor® in acetonitrile at a suitable temperature or using methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)piperidin-4-one 48. Ring expansion of 48 to ethyl 6-fluoro-1-(4-nitro-1H-pyrazol-5-yl)-5-oxoazepane-4-carboxylate 49 may be achieved using ethyl diazoacetate and boron trifluoride diethyl etherate in a suitable solvent such as dichloromethane at suitable temperatures or using methods described in the literature. Decarboxylation of 49 by heating with hydrochloric acid at a suitable temperature or by methods described in the literature to give 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-one 50. Reductive amination of 50 by methods described in the literature gives 3-fluoro-1-(4-nitro-1H-pyrazol-5-yl)azepan-4-amine 51. The amine of 51 can be protected with a suitable protecting group such as trifluoroacetamide using trifluoroacetic anhydride with diisopropylethylamine in a suitable solvent such as dichloromethane, or using other methods described in the literature, to give amine-protected 52.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(Br)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 22 h
Yield: 49.1 %

Procedure:
A solution of 3.06 g of 5-bromo-2'-deoxycytidine and 2.3 g of p-toluenesulfonyl chloride in 50 ml of pyridine was stirred at 4° C. for 24 hours. An additional 1.91 g of p-toluenesulfonyl chloride were added and stirring was continued at 4° C. for an additional 22 hours. 20 ml of methanol were added, the mixture was stirred at room temperature for 30 minutes and then evaporated. The crude product was subjected to flash chromatography on a column of silica gel using ethyl acetate/methanol (9:1) for the elution, there being obtained 2.26 g of 5-bromo-2'-deoxy-5'-O-p-toluenesulfonylcytidine in the form of a white solid of melting point 168° C. (decomposition).
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH:3]=[CH:4][CH3:5].[CH:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH3:5][C@H:4]1[C@@H:9]2[CH2:10][C@H:11]([CH:7]=[CH:8]2)[C@@H:3]1[C:2](=[O:6])[CH3:1]
Reactant: C1=CCC=C1
Reactant: CC=CC(C)=O
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 85 %

Procedure:
Prepared according to general procedure A from 3-penten-2-one (68 μL, 0.70 mmol), cyclopentadiene (69 μL, 0.84 mmol), 70% aqueous perchloric acid (12.1 μL, 0.14 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (37.8 mg, 0.14 mmol) in water (175 μL) for 2.5 hours at 0° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a colorless oil in 85% yield (89 mg, 0.59 mmol); 14:1 endo:exo, endo 61% ee. IR (film) 3061, 2962, 2871, 1708,1461, 1426, 1359,1333, 1267, 1183, 1170,114, 1095, 1055,906.8, 797.8, 719.4, 654.5, 597.0 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.21 (dd, J=6.0, 3.3 Hz, 1 H, CH═CH), 5.90 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.13 (m, 1H, CHCH═CH), 2.44 (m, 1H, CHCH═CH), 2.42 (dd, J=4.8, 3.9 Hz, 1H, CHCO), 2.10 (s, 3H, CH3CO), 1.86 (m, 1 H, CHCH3), 1.57 (m, 1H, C(H)H), 1.43 (m, 1H, C(H)H), 1.14 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 209.2, 138.8, 132.6, 61.9, 49.3, 46.6, 46.5, 35.9, 29.5, 21.4; HRMS (CI) exact mass calc'd for (C10H14O) requires nm/z 150.1045, found m/z 150.1041. [α]D=+70.4 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (120° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=6.9 min, and (1S, 2S, 3R, 4S) endo isomer tr=6.3 min, exo isomers tr=5.7, 5.5 min.
Reaction SMILES: [N:1]1([C:15](=[O:18])[CH2:16][CH3:17])[C@H:10]2[C@@H:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[N+:19]([O-])([OH:21])=[O:20].O.S(=O)(=O)(O)O>[N+](C)([O-])=O>[N+:19]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][C@@H:10]3[C@H:5]([CH2:4][CH2:3][CH2:2][N:1]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][C:7]=2[CH:14]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)N1CCC[C@@H]2Cc3ccccc3C[C@H]21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)N1CCC[C@@H]2Cc3cc([N+](=O)[O-])ccc3C[C@H]21
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
2.5 g trans-1-(3,4,4a,5,10,10a-Hexahydro-2H-benzo[g]quinolin-1-yl)-propan-1-one (10.27 mmol) were dissolved in 25 ml nitromethane. At −5° C. to −10° C., a mixture of 0.71 ml of nitric acid (10.27 mmol), 1.5 ml of water, and 9.5 ml of sulphuric acid (170 mmol) were added within 30 minutes. Stirring continued for 1.5 h under cooling conditions before the mixture was poured onto crushed ice. The aqueous phase was extracted twice with ethyl acetate, the combined organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 2.7 g of the nitrated product as a mixture of several nitro-isomers, which was used in the subsequent reaction without further separation.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1.Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: OB(O)c1cc(CN2CCOCC2)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (Example 129, Step 3) (2.00 g, 8.33 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.501 g, 3.47 mmol), Am-Phos (Aldrich, 0.124 g, 0.175 mmol) and potassium acetate (Aldrich, 1.14 g, 11.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 10 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. After the reaction mixture was cooled to room temperature, insoluble material was removed via filtration. The filtrate was partitioned between saturated aqueous sodium chloride (60 mL) and 10% isopropanol in chloroform (60 mL). The aqueous phase was extracted with 10% isopropanol in chloroform (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 25%) to afford 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.27 g, 26% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (dd, J=9.00, 2.35 Hz, 1H) 8.27 (s, 1H) 5.83 (br. s., 2H) 3.70-3.75 (m, 4H) 3.56 (s, 2H) 2.54 (s, 3H) 2.44-2.50 (m, 4H). m/z (ESI, positive ion): 305.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([CH2:30][NH2:31])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([CH2:30][NH:31][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])[CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(CN)C(=O)N3CCCC3)ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CNCC(C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C

Procedure:
Prepared analogously to Example 1k from 2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and ethyl bromoacetate/potassium carbonate in acetone.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (139.5 mg, 1.66 mmol) in 8.1 mL water was added 2-aminoethanethiol hydrochloride (101.2 mg, 0.89 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25b (155.1 mg, 0.81 mmol) in 8.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 72.6 mg (36% from 24b) of clean 26b as a colorless oil.
Reaction SMILES: [ClH:1].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:12]([O:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3]>[Pd].C(O)C>[ClH:1].[C:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][C:17](=[O:26])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)c2ccc(OC)cc2)cc1
Yield: 51.5 %

Procedure:
By catalytic hydrogenation of 12.0 g of 3,4-bis(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 300 ml.of anhydrous ethyl alcohol in the presence of 2.0 g. of 10 percent palladium-on-charcoal catalyst there was obtained 6.2 g of 3,4-bis(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 165° C. (uncorr.). The solubility of this salt in polyethyleneglycol 200 at 25° C. was less than 1 percent. When 1 percent solutions of this salt in each of dimethyl sulfoxide and glycerol formal were diluted with three volumes of water, no precipitate formed.