Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10]([O:13][CH:14]=[CH2:15])(=[O:12])[CH3:11]>C1CCCCC1>[C:10]([O:13][CH2:14][CH2:15][Sn:5]([CH2:15][CH2:14][O:13][C:10](=[O:12])[CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:12])[CH3:11]
Reactant: C=COC(C)=O
Reactant: CCCC[SnH2]CCCC
Solvent: C1CCCCC1
Product: CCCC[Sn](CCCC)(CCOC(C)=O)CCOC(C)=O

Procedure:
2.349 g (0.01 mole) of dibutyltin dihydride, 1.722 g (0.02 mole) of distilled vinyl acetate and 2 g of anhydrous cyclohexane were introduced into a Pyrex® vessel thermostated at 25° C. The solution was exposed to ultraviolet rays for 3 hours. The cyclohexane was then removed under vacuum at ambient temperature. The expected product was obtained pure in quantitative yield.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.C[Li].[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=3)([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)([F:21])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH2:29][C:30]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=4)([C:31]([F:32])([F:33])[F:34])[O:35][CH:1]=3)=[CH:26][CH:27]=2)([F:21])[CH2:18]1)=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a stirred solution of trimethylsilyldiazomethane (2M in diethyl ether, 18.64 mL, 37.289 mmol) in 1,2-dimethoxyethane (DME, 100 mL) was added methyl lithium (1.6M in diethyl ether, 23.32 mL, 37.289 mmol) at −78° C. over period of 10 minutes and stirred reaction mixture for 30 minutes at −78° C. Pre-dissolved 3-{4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Intermediate 1) (5 g, 9.322 mmol, 1eq.) in DME (50 mL) was added at −78° C. in drop wise manner over period of 10 minutes. Resulting reaction mixture was stirred for 1 hour at same temperature and then at room temperature for 2 hours. Acetic acid (1.60 mL, 27.967 mmol, 3 eq.) was added at room temperature over period of 5 minutes followed by addition of TBAF (27.92 mL, 27.967 mmol, 3 eq.) at room temperature over period of 10 minutes. After consumption of starting material, reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (5×150 mL). Combined organic layer was dried over sodium sulphate and concentrated in vacuo to get orange semisolid (6.1 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 10% ethyl acetate in hexane to afford off white semisolid (1.6 g, Impure). The product was again purified by trituration using DCM: pentane (1:5, 2×20 mL) to afford product as off white solid (0.45 g, 9.18%). Yield: −0.45 g (9.18%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.20 (d, J=17.24 Hz, 1H), 3.30 (d, J=17.24 Hz, 1H), 4.14-4.21 (m, 2H), 4.33-4.41 (m, 2H), 7.32-7.38 (m, 4H), 7.40 (t, J=1.78 Hz, 1H), 7.52 (d, J=1.36 Hz, 2H). LC-MS (m/z): =529.9 (M−H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]C)=O)[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2].[NH3:24]>CO>[CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:24])=[O:19])[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2]
Reactant: N
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 0.771 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.86 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:12]1[CH:14]2[CH2:15][C:16]3[C:21]([CH:13]12)=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3>CN(C=O)C>[C:1]([NH:9][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:15][C@H:14]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of a benzamide (2 parts) in DMF is treated with NaH (2 parts) and the reaction is stirred until gas evolution ceases. To the reaction is added 1,2-epoxy-6-nitroindane (1 part) and the reaction is stirred over night at 60° C. The reaction is poured into ice-water and extracted with CH2Cl2. The organic extracts are washed with water, dried, and the solvent evaporated. The residue is chromatographed to obtain trans-1-benzamido-2-hydroxy-6-nitroindane. To a solution of the nitroindane (1 part) in a mixture of pyridine (16 parts), 4-dimethylaminopyridine (0.15 parts) and an inert organic solvent such as THF or CH2Cl2, acetyl chloride (1.2 parts) is added dropwise. After several hours, the reaction is treated with cold water and the organic layer separated. The organic solution is washed with cold 1 N HCL, the organic layer dried, and the solvent is evaporated to give trans-1-benzamidoamido-2-acetoxy-6-nitroindane. Processing of this protected indane as in Preparation 2 provides the trans-1-benzamido-2-hydroxy-6-carboxamido-indane.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH:29]=[CH:30][C:26]([CH3:25])=[N:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc[nH]n1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)n1
Yield: 27.8 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (371 mg, 1.0 mmol), 3-methyl-1H-pyrazole (164 mg, 2.0 mmol) and DMAP (367 mg, 3.0 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 116 mg (28%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.39-1.57 (m, 4 H), 1.59 (s, 9 H), 2.17 (s, 3 H), 2.23-2.33 (m, 1 H), 3.27-3.36 (m, 2 H), 3.88 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 6.31 (d, J=2.54 Hz, 1 H), 7.88-7.99 (m, 2 H), 8.18 (d, J=2.73 Hz, 1 H), 8.28 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=416.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[NH2:56][NH2:57]>>[CH2:22]([O:21][N:16]1[C:17]([CH3:19])([CH3:20])[CH2:18][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]3[CH2:42][C:41]([CH3:43])([CH3:44])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]3)[N:3]=[C:2]([NH:56][NH2:57])[N:7]=2)[CH2:14][C:15]1([CH3:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NN
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NN)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and hydrazine.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C

Procedure:
20 g (110.4 mmol) of 2-methyl-3-nitrobenzoic acid is refluxed in 100 ml of methanol for 10 hours after 2 ml of concentrated sulfuric acid is added. The product that crystallizes out during cooling is suctioned off and dried. The filtrate is evaporated to the dry state, the solid residue is taken up in ethyl acetate, and the solution is washed twice with saturated sodium bicarbonate solution. After drying on Na2SO4, another product is obtained. Together, 16.4 (76.3%) of the desired compound is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3nc(C(F)(F)F)cn23)nc1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C(F)(F)F)cn23)nc1

Procedure:
In analogy to the procedure described for Example 7, 11.4 mg (33% of theory) of the product are obtained as a solid starting from 29 mg (0.07 mmol) of 6-[(2-{[7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethyl)amino]nicotinonitrile (Example 24A) by coupling with 13 mg (0.07 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][CH:6]=1.[CH2:7]([O:9][C:10](=[O:32])[N:11]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[CH3:8]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:9][C:10](=[O:32])[N:11]([C:21]1[CH:26]=[C:25]([C:4]2[O:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[CH3:8]
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: Cc1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(-c2nc(C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methyl-oxazole (40 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano-benzyl)-carbamic acid ethyl ester (100 mg) and palladium bis(triphenylphosphine)dichloride (30 mg), giving the product (65 mg) as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:10][C:11]([C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[C:16]2=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@H:5]([NH:10][C:11]([C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[C:16]2=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCC[C@H](CN=[N+]=[N-])NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](CN)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 mg of N-[(2R)-1-azidohexan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide (Example 44A, 0.095 mmol) were initially charged in 0.78 ml of THF/water (10:1.5), 28.3 mg of triphenylphosphine (0.108 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was purified by preparative thick-layer chromatography (mobile phase ethyl acetate:dichloromethane:diethylamine=2:1:0.1). The combined product fractions were purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated. This gave 17 mg of the title compound (41% of theory).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.10 g, 9.35 mmol) in carbontetrachloride (30 mL), add N-bromosuccinimide (1.75 g, 9.83 mmol) and benzoylperoxide (3 mg) and stir at reflux for 1 hour. Cool the reaction mixture, filter, wash with water and brine. Dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound as an amber oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.Cl.[NH2:15][CH2:16][CH2:17][SH:18]>CCO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[NH:15][CH2:16][CH2:17][S:18]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Reactant: NCCS
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1csc(-c2ccc(C3NCCS3)cc2)c1
Yield: 13.6 %

Procedure:
To a solution of 4-(2-thienyl)benzaldehyde (500.0 mg, 2.66 mmol) in EtOH (5.0 mL) was added a solution of cysteamine HCl (101.0 mg, 0.89 mmol) in water (2.0 mL) dropwise with stirring. The solution was then stirred at room temperature for 18 hours before the bulk of the EtOH was removed by rotary evaporator. The resulting residue was diluted with water (15.0 mL) and extracted with ether (3×30.0 mL) to remove excess aldehyde. The acidic aqueous layer was then basified with the slow addition of solid sodium carbonate (300.0 mg) to afford a white precipitate, which was filtered and washed carefully with water (3×20.0 mL). The solid was dried under reduced pressure to afford 2-[4-(2-thienyl)phenyl]-1,3-thiazolane (15) as a yellow powder (30 mg, 4.6%). 1H nmr (CDCl3, 300 MHz) 3.14, m, H4,4,5; 3.64, m, H5; 5.95, s, H2; 7.08, m, thienyl-H; 7.31, m, 2×thienyl-H; 7.50, d (8.1 Hz), 2×phenyl-H; 7.59, d (8.4 Hz), 2×phenyl-H. ESI (+ve) MS m/z 248 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:39]([C:36]4[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:43])[F:44])=[CH:38][CH:37]=4)(=[O:41])=[O:40])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.300 g (0.925 mmol) of {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester, and 8 mL of dichloromethane was added 0.112 mL (1.39 mmol) of pyridine, 0.271 g (1.11 mmol) of 4-Trifluoromethyl-benzenesulfonyl chloride and 0.004 g (0.0277 mmol) DMAP. The dark orange solution was stirred at r.t. for 4 h. The mixture was extracted with dichloromethane, then washed with water, 1 N HCl, and brine. Dried with Na2SO4. Purified on silica gel (EtOAc/Heptane, 9:1 to 6:4) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d6) 0.99-1.10 (m, 2H) 1.34-1.46 (m, 2H) 1.71-1.82 (m, 5H) 2.14 (d, J=6.82 Hz, 2H) 2.39 (tt, J=−12.16, 3.25 Hz, 1H) 3.57 (s, 3H) 7.16 (d, J=8.34 Hz, 2H) 7.54 (dd, J=2.53, 1.77 Hz, 2H) 7.61 (d, J=8.34 Hz, 2H) 7.73 (d, J=8.34 Hz, 2H) 7.78 (d, J=8.08 Hz, 2H) 8.14 (dd, J=2.27, 1.01 Hz, 1′H).
Reaction SMILES: [O:1]1CCC(C(O)=O)C1.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[CH:18]1([NH:17][C:16](=[O:1])[NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol; 1 equiv.) in 25 mL anhydrous dichloromethane was added 7.85 g of dicyclohexylcarbodiimide (38 mmol; 1.4 equiv.) and 4.54 mL triethylamine (32.6 mmol; 1.2 equiv.). N-methyl-20 methanolamine hydrochloride was then added, followed by 60 mg of DMAP (4-dimethylamino)pyridine. An exothermic reaction ensued and a further 25 mL of dichloromethane were added. The mixture was stirred at ambient temperature overnight, then filtered through diatomaceous earth and concentrated. The residue was treated with ether and the white solid filtered off and removed. The solvent was removed from the mother liquor and the residue purified by column chromatography on SiO2 using 15-25% EtOAc in hexanes as eluent mixtures to provide the desired amide as a colorless oil (55% of theoretical yield) that still contained 10% of dicyclohexyl urea. This was used without further purification in the next reaction.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][O:21]C(=O)C2C=CC=CC=2)[CH2:18][C@@H:17]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[C@H:16]([OH:40])[CH2:15]1)(=O)C1C=CC=CC=1.CO.Cl>C1COCC1>[OH:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][OH:21])[CH2:18][C@@H:17]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[C@H:16]([OH:40])[CH2:15]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](CO)C[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.4 %

Procedure:
Sodium methoxide (40 mg, 0.74 mmole) was added to a solution of 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (185 mg, 0.37 mmole) in a solvent mixture consisting of anhydrous methanol (4 ml) and anhydrous THF (4 ml) under ice cooling. After stirring the resulting mixture at room temperature for 5 hours, the reaction mixture was neutralized with dilute hydrochloric acid, and the solvent was distilled off therefrom under reduced pressure. The residue was purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(hydroxymethyl)-2-hydroxycyclohexyl]-adenine (109 mg, Yield 100%).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>[Ag]=O.O>[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[C:6]([OH:1])=[O:7]
Reactant: Cc1cc(F)c(C=O)c(F)c1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Silver oxide (43.8 g, 0.189 mol) was placed in a flask along with water (200 mL) and sodium hydroxide (33.7 g, 0.842 mol). To it was added 2,6-difluoro-4-methylbenzaldehyde (29.23 g, 0.187 mol) in small portions over a 30 min period. After a vigorous exothermic reaction, the color of the reaction mixture changed from black to gray. Resulting thick suspension was stirred for 1 hr, filtered through a Buchner funnel. The filtrate was acidified to pH 2 with concentrated HCl to give a suspension. The precipitate was collected by suction filtration, dissolved in ether and dried over anhydrous Na2SO4, filtered and concentrated to give white solid (17.0 g, 53%). 1H-NMR (500 MHz, d6-DMSO): δ13.7 (br.s, 1H), 7.02 (d, 2H, J=9.3 Hz), 2.32 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:17][CH:16]([CH2:18]Br)[O:15][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][C:7]2([CH3:14])[CH3:13].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:18][CH:16]1[O:15][C:5]2=[C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[C:4]2[CH2:17]1)[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:14])[CH3:13])=[N+:21]=[N-:22]
Reactant: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CBr)C3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN=[N+]=[N-])C3
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.4 %

Procedure:
5-Bromo-2-bromomethyl-9,9-dimethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.25 g, 3.21 mmol) was dissolved in dimethylformamide (50 ml). To the resultant solution, sodium azide (1.25 g, 19.3 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted along with chloroform and water. The organic phase was dried, and condensed under reduced pressure. Recrystallization from chloroform-n-hexane-ether yielded 997 mg of the title compound as pale yellow needles (88.4%).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1.O>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH2:3])=[CH:7][CH:8]=2)=[N:15][CH:16]=1
Reactant: NCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Sodium hydride/60 percent oil dispersion (0.72 mg, 18 mmol) was added in portions to a slurry of tyramine (2.1 g, 15 mmol) in anh. DMF (25 mL). After 15 minutes, 2-chloro-5-(trifluoromethyl)pyridine (2.9 g, 16 mmol) was added neat and the reaction heated to 50° C. for 3 hours. After cooling, the reaction was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic portions were combined and washed with brine (50 mL) and dried (Na2SO4). Filtration and removal of solvent left a brown residue that partially solidified. This was triturated in minimal ethyl acetate and collected by filtration, leaving product as a white solid, 3.0 g, 10.6 mmol, 71 percent yield.
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:24]([N:21]1[CH2:22][CH2:23][C@H:19]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: ClCCN1CCOCC1
Reactant: CC(=O)N1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)C1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CC[C@H](N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)C1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-1-[1-(acetyl)-pyrrolidin-3 (S)-yl]-urea, dithioerythritol and N-(2-chloroethyl)morpholine