Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CCO.CC(N(C)C)=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH:35][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 81.2 %

Procedure:
2,4-Dichloro-5-nitro-pyridine (500 mg, 2.59 mmol) was dissolved in EtOH-DMA (15 mL, 1:1). To this solution was added diisopropylethyl amine (0.99 mL, 5.7 mmol) followed by 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (611 mg, 2.85 mmol). The reaction was stirred for 18 h, then concentrated in vacuo. The crude residue was rediluted in EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude residue was purified by SiO2 flash chromatography eluting with 2% CH3OH—CH2Cl2 to afford 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (780 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:11][CH2:12][OH:13].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([O:13][CH2:12][CH2:11][CH2:10][C:9]([F:18])([F:8])[C:14]([F:15])([F:16])[F:17])(=[O:22])=[O:21]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Trietylamine (46 ml, 0.330 mol) was added to a solution of 4,4,5,5,5-pentafluoropentan-1-ol (25 g, 0.132 mol) in dichloromethane (50 ml). To this solution, methanesulfonyl chloride (20.4 ml, 0.264 mol) was added at 0° C., followed by stirring for 3 hours at room temperature under argon atmosphere. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with 1N aqueous hydrochloric acid, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (34 g, quantitative).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([N:21]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[S:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)(=[O:24])=[O:23])[C:17]([NH:19][OH:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:20][NH:19][C:17](=[O:18])[C@H:16]([N:21]([CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: CC(C)CCN([C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NO)S(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCN([C@H](Cc1ccc(O)cc1)C(=O)NO)S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 6 h
Yield: 20.9 %

Procedure:
A mixture of (R)-3-(4-benzyloxy-phenyl)-N-hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-propionamide (230 mg, 0.42 mmol) and 200 mg of 10% Pd/C in ethyl acetate (20 mL) are hydrogenated under 50 PSI for 6 h. The reaction mixture is filtered through celite, and concentrated in vacuo. Purification by flash chromatography yields 40 mg of product. 1HNMR (400 MHz, MeOD): δ 0.90 (d, 6H, J=5.5 Hz), 1.5-1.7 (m, 4H), 2.4-2.5 (dd, 1H, J=5 Hz), 3.05-3.15 (dd, 1H, J=5 Hz), 3.35-3.45 (m, 1H), 3.6-3.75 (m, 1H), 4.30-4.40 (q, 1H, J=5 Hz), 6.55 (d, 2H, J=8 Hz), 6.80 (d, 2H, J=8 Hz), 7.7-7.85 (m, 3H), 7.92-8.10 (m, 3H), 8.45 (s, 1H). LCMS (m/z): 457 (M+1). Analytics calculated for C24H28N2O54S: C, 63.14; H, 6.18; N, 6.14. Found: C, 63.03; H, 6.30; N, 5.89.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>CO>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:1])=[O:21]
Reactant: O=C(O)Cc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)Cc1ccccc1F
Yield: 22016.1 %

Procedure:
p-Toluenesulfonic acid (20 mg) was added to a solution of 2-fluorophenyl acetic acid (3.8 g, 24.65 mmol) in methanol (29 ml). After heating the reaction mixture for 1 h on the steam bath, the solvent was removed in vacuo. Filtration through a pad of silica gel (ethyl acetate/hexanes 10/90) gave methyl 2-fluorophenylacetate (4.3 g) as an oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]4[CH2:20][CH2:21][CH:22]([NH:25][C:35](=[O:36])[CH2:34][C@H:31]5[CH2:32][CH2:33][C@H:28]([O:27][CH3:26])[CH2:29][CH2:30]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)NC2CCC(CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (30.8 mg, 77.7%), MS (ISP) m/z=485.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 0.085 mmol) and trans-(4-methoxycyclohexyl)acetic acid synthesized as described in W2009/013212 p. 73.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:4][N:3]=1.[BrH:27].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:27][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[CH:4][N:3]=1
Reactant: Br
Reactant: CCCCCCCCCCCCCCCCCCCc1ccnc(N)c1
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCc1ccnc(Br)c1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
Powdered 2-amino-4-nonadecylpyridine (110.6 g, 0.31 mol) was added under vigorous stirring in portions to 48% hydrobromic acid (500 mL) at 20 to 30° C. in a 4-L glass reactor. After all of the compound was dissolved, the mixture was cooled at −20° C. To this suspension was added cooled bromine (44.3 mL, 0.86 mol) dropwise over 30 min, maintaining the temperature at −20° C. The resulting paste was stirred for 90 min at this temperature. Then sodium nitrite (56.6 g, 0.82 mol) in water (250 mL) was added dropwise. After that the reaction mixture was allowed to warm to 15° C. over 1 h and was stirred for an additional 45 min. The mixture was cooled to −20° C. and treated with cooled aqueous NaOH (222 g, 330 mL H2O). During the addition the temperature was kept at −10° C. maximum. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was extracted with ethyl acetate, the organic phase was dried with Na2SO4, and the solvent was removed in vacuo. The residue was subjected to distillation in vacuo to yield the desired. Yield 50%. Anal. Calcd for C24H42BrN: C, 67.90; H, 9.97; N, 3.30. Found: C, 67.50; H, 9.87; N, 3.40. MS (ESIMS): m/z: 423.3.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[N:14][C:13]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:12]2)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:22]([O:21][C:15]1[C:16]2[C:11](=[CH:10][C:9]([OH:8])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:13]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1)([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Yield: 106.2 %

Procedure:
A mixture of (6-benzyloxy-1-isopropoxy-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (300 mg), 10% Pd/C (50 mg) and MeOH (80 ml) was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen at room temperature. Then the mixture was passed through a celite pad and the filtrate was concentrated and dried to give 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (250 mg). LC-MS: m/e 329 (MH+).
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[F:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=O>CN(C)C=O>[F:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1/[CH:26]=[CH:1]\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1F
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cnccc1/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 10 %

Procedure:
Diethyl benzylphosphonate (2.8 ml, 13.4 mmol) was added to a solution of sodium methoxide (0.75 g, 13.6 mmol) in anhydrous dimethylformamide (15 ml) and the resultant mixture stirred at room temperature, under nitrogen, for ten minutes. A solution of 3-fluoropyridine-4-carboxaldehyde [prepared by the method of F. Marsais and G. Queguiner, Tetrahedron, 1983, 39, 2009] (1.55 g, 12.4 mmol) in anhydrous dimethylformamide (10 ml) was added and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction mixture was poured into ice-water (125 ml), the precipitated solid collected under suction and washed with water. The aqueous filtrate was extracted with ethyl acetate (100 ml), the extract dried (MgSO4) and concentrated in vacuo to an off. This off and the solid product were combined and purified by flash chromatography, eluting with 1:2 then 1:1 ethyl acetate/petrol (60°-80° C.), to afford (Z)-3-fluoro-4-(2-phenylethenyl)pyridine (0.25 g, 10%) as a colourless off; δH (CDCl3) 6.55 (1H, d, J 12.3Hz, CH=CHPh), 6.92 (1H, d, J 12.3Hz, CH=CHPh), 7.10 (1H, t, J 5.6Hz, ArH), 7.18-7.27 (5H, m, ArH), 8.18 (1H, d, J 4.9Hz, 6-H) and 8.43 (1H, s, 2-H); and (E)-3-fluoro-4-(2-phenylethenyl)pyridine (0.69 g, 28%) as a white solid; δH (CDCl3) 7.20 (1H, d, J 16.5Hz, CH=CHPh), 7.33-7.43 (4H, m, CH=CHPh and ArH), 7.51 (1H, m, ArH), 7.57 (2H, m, ArH), 8.37 (1H, d, J 5.1Hz, 6-H) and 8.47 (1H, d, J 2.2Hz, 2-H).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3([CH:12]([NH2:13])[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1
Reactant: N#CC1(N2CC3(COC3)C2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CC3(COC3)C2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=259.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-cyclobutanecarbonitrile (intermediate AF) and phenyllithium.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].[NH3:15].CO>>[NH2:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: N
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Solvent: CO
Product: N#Cc1cc(CN)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
3-Bromomethyl-5-trifluoromethyl-benzonitrile (which is prepared in Reference Example 12) (15.9 g) is dissolved in 7M-ammonia/methanol (550 ml), and the mixture is stirred at 50-60° C. for 30 minutes. The reaction solution is concentrated under reduced pressure. To the resulting residue are added a saturated aqueous sodium bicarbonate solution and chloroform, and the mixture is separated, and the organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1→chloroform:methanol:ammonium hydroxide solution=19:1:0.1) to give 3-aminomethyl-5-trifluorometyl-benzonitrile (10.4 g). MS (m/z): 201 [M+H]+
Reaction SMILES: C(Cl)Cl.N1C=CC=CC=1.[CH2:10]([O:17][C:18]1[C:19]([CH3:33])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C@:23]([CH3:32])([CH2:30][OH:31])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[C:19]([CH3:33])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C@:23]([CH3:32])([CH:30]=[O:31])[CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CO)O2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(C=O)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred mixture of 36 ml. of dry CH2Cl2, 2.8 ml. of dry pyridine and 1.46 g. (14.6 mmol) of CrO3 was added a solution of 645 mg. (1.98 mmol) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanol in 5 ml. of CH2Cl2. The dark mixture was stirred for 40 min. at room temperature then the organic solution was decanted and the dark residue was washed with ether and CH2Cl2. The combined organic solutions were diluted with ether, washed with 1 N NaOH, H2O and 1 N HCl and work-up was then completed in the usual manner. The yellow oily product (590 mg.) was chromatographed on 50 g. of silica gel. Elution with 19:1 (parts by volume) hexane-ether gave 492 mg. (76.7%) of pure (S)-(+)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-carboxyaldehyde as an oil which crystallized yielding a colorless solid, mp 56°-58°; [α]25D+11.89° (c 5.2, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]3[CH2:13][CH2:12][CH2:11][C:10](=[O:23])[C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(O)C.[BH4-].[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]3[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC2=C1C(c1cccc(Br)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc(Br)c1)C1=C(CCCC1)N2
Yield: 99.7 %

Procedure:
To a stirred 70° C. mixture of 9-(3-bromophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (5.0 g, 13.4), ethanol (120 mL) and pyridine (40 mL) was added sodium borohydride (7.5 g) in three portions over six hours. The solvent was removed; the resulting yellow solid washed well with water and air dried to provide the title compound (4.8 g). Recrystallization from ethanol/hexane returned analytically pure yellow solid, mp 258°-260° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.09-2.15 (m,4, CH2), 2.39-2.45 (m,2, CH2), 4.17 (s,1, CH), 7.16-7.21 (m,2, Ar), 7.26-7.29 (m,2, Ar), 8.44 (s,1, NH); (CI, CH4) MS: m/z=360(M+1). Analysis for C19H20BrNO: Calculated C, 63.69; H, 5.59; N, 3.91; Found: C, 63.73; H, 5.69; N, 3.94.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[NH:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[NH:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)CC1CCCCCCC(CS)NC1=O
Solvent: ClCCl
Product: O=C(O)CC1CCCCCCC(CS)NC1=O
Reaction time: 8 h

Procedure:
10-Mercaptomethyl-3-t-butoxycarbonylmethyl-2-oxo-1-azacyclodecane (0.21 g, 0.69 mmol) is dissolved in methylene chloride (15 mL). Gaseous hydrogen chloride is bubbled through the solvent for 15 minutes, and then the reaction is sealed and stirred overnight. The solvent is evaporated the next day to give 10-mercaptomethyl-2-oxo-1-azacyclodecane-3-acetic acid, MS: M+1=260.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:34]/[C:33]2[CH:36]=[CH:37][C:30]([Br:29])=[CH:31][CH:32]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/c2cccc(Br)c2)cc1
Reaction time: 0.05 h

Procedure:
A solution of 38.0 g of (3-bromo-benzyl)-triphenylphosphonium bromide, known from the literature, in 250 ml of tetrahydrofuran was treated at -10° C. with 8.75 g of potassium tert.-butylate and stirred for 3 minutes. A solution of 14.8 g of 4-bromobenzaldehyde was added dropwise to the yellow-orange suspension within 15 minutes. After stirring for 60 minutes the reaction mixture was concentrated. The residue was treated with ice-water and extracted with ethyl acetate/ether. The organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica gel with hexane and hexane/ether 99:1 and gave (E)-3,4'-dibromostilbene as colourless crystals, MS: m/z 338 (M+), as well as (Z)-3,4'-dibromostilbene as a colourless oil, MS: m/z 338 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]([O:16][C:17]([NH:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][CH2:21]1)=[O:18])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:24]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:19][C:17](=[O:18])[O:16][C:13]([CH3:14])([CH3:12])[CH3:15])[CH2:25]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2cnccc2[N+](=O)[O-])C1
Yield: 65 %

Procedure:
The method of Example 88 (Method 4) was followed using 1 eq each of 3-bromo-4-nitropyridine-N-oxide, 3-N-Boc-amino piperidine and diisopropylethylamine yielding tert-butyl 1-(4-nitropyridin-3-yl)piperidin-3-ylcarbamate (65%). LCMS (m/z): 339.1 (MH+); LC Rt=2.88 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>CN(C=O)C.CCOC(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of phenol (2.35 g, 25.0 mmol) and K2CO3 (9.4 g, 68.1 mmol) in 40 mL of DMF was heated at 100° C. with 4-bromo-1-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 15% EtOAc/hexane giving a yellow oil (6.6 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.[Cl:45][C:46]1[CH:47]=[C:48]([N:52]2[CH:56]=[C:55](B(O)O)[CH:54]=[N:53]2)[CH:49]=[CH:50][CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23]([C:55]4[CH:54]=[N:53][N:52]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([Cl:45])[CH:47]=5)[CH:56]=4)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cnn(-c2cccc(Cl)c2)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cnn(-c5cccc(Cl)c5)c4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Yield: 77.4 %

Procedure:
A dried pressure tube was consecutively charged with (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate B9.1) (199 mg, 299 μmol), 1,2-dimethoxyethane (4 ml), 1-(3-chlorophenyl)-1H-pyrazol-4-ylboronic acid (CAS 1072945-88-0) (102 mg, 448 μmol), and a solution of potassium carbonate (2M, 448·1). The tube was flushed with argon, thereafter tetrakistriphenylphosphinepalladium(0) (17.3 mg, 14.9 μmol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (177 mg, 77% yield) was obtained as a white foam. MS (ISP): m/z=765.4 [M+H]+ and 767.4 [M+2+H]+.
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH2:9][N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:20]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[CH2:5]1)(=O)C.[CH2:29]([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH:30]=[CH2:31]>C(O)CCC>[CH2:29]([N:32]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:11]1[C:12]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:20]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH:30]=[CH2:31]
Reactant: C=CCNC1CCCCC1
Reactant: CC(=O)N1CN(C(C)=O)C2C(=C1Cl)N(C(C)=O)CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCCCO
Product: C=CCN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C1CCCCC1
Yield: 59 %

Procedure:
10 g. triacetyl-6-chloro-9-(β-D-ribofuranosyl)-purine and 10 g. allyl-cyclohexylamine were heated under reflux for 1 hour in 100 ml. butanol. The butanol was then distilled off in a vacuum, the residue was dissolved in chloroform and the chloroform solution was then shaken out successively with dilute hydrochloric acid, dilute aqueous sodium bicarbonate solution and water. The chloroform solution was then dried over anhydrous sodium sulfate and evaporated to a syrup. This was dissolved in methanol and the solution, after the addition of 5 ml. 1N sodium methylate solution was heated for 10 minutes on a steambath. After cooling, the solution was distilled off to dryness, the residue was dissolved in chloroform and the chloroform solution was washed with water. The organic phase was dried and evaporated and the residue obtained recrystallized from ethanol. 6.1 g. (59% of theory) N(6)-allyl-N(6)-cyclohexyl-adenosine were obtained; m.p. 123° - 125° C.