Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][C@H:14]3[C@@H:16](O)[CH2:17][CH2:18][N:13]3[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:27])CC>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][CH:14]3[C@H:16]([F:27])[CH2:17][CH2:18][N:13]3[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(N2C[C@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl
Solvent: ClCCl
Product: Cc1c(N2CC3[C@H](F)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.9 %

Procedure:
A solution of (7S,7aS)-2-chloro-4-(7-hydroxy-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (WO 03/096980) (30 mg, 0.103 mmol) in dry dichloromethane (1.0 mL) was cooled to −65° C., treated with DAST (26 μL, 0.21 mmol) and stirred for 17 h, allowing the temperature to warm to rt. The reaction mixture was then cooled to 0° C., quenched with 10% sodium carbonate (0.5 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was washed with H2O (0.5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The syrup was combined with a previous batch (5.4 mg) and chromatographed 3× (silica gel; EtOAc/hexane gradient then CH3OH/CH2Cl2 gradient) to yield the title compound (14.5 mg, 47.9%). HPLC: 99.1% at 2.04 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3C—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=20.8 min (100%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 60 min at 1 mL/min. MS (ES+): m/z 294 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine. pyrimidine.
Reaction SMILES: I(C1C=CC=CC=1)=O.B(F)(F)F.[CH3:13][CH2:14][O:15]CC.[CH2:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][Si](C)(C)C)=[CH2:27])=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]>C(O)C>[CH2:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26](=[O:27])[CH2:28][O:15][CH2:14][CH3:13])=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: C=C(O[Si](C)(C)C)c1ccc(CC(C)C)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=Ic1ccccc1
Solvent: CCO
Product: CCOCC(=O)c1ccc(CC(C)C)cc1
Temperature: -70 °C
Yield: 95.7 %

Procedure:
Iodosylbenzene (2.18 g) was dissolved in ethanol (45 ml), and boron trifluoride etherate (2.55 g) was added. The mixture was stirred at -70° C., and then 4-isobutyl-α-trimethylsilyloxystyrene (2.24 g) was added. The mixture was stirred at -70° C. for 30 minutes, and then the temperature was slowly raised to room temperature. The ethanol was evaporated and water was added. The mixture was neutralized with aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel column eluting with hexane-ethyl acetate (94:6) to give 4'-isobutyl-2-ethoxyacetophenone (1.90 g) as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[S:14])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1.[CH3:23]I>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([S:14][CH3:23])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1
Reactant: CI
Reactant: CN1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Temperature: 6 °C

Procedure:
The reaction vessel was charged with 11.5 grams (479 moles) of sodium hydride (99%) and 850 ml of dry N,N-dimethylformamide. To this mixture, 132 grams (437 moles) of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,3,4-benzotriazepine-2-thione (Example 15) was added with stirring using a screw feed solid addition apparatus while the system was flushed with dry nitrogen. Thirty minutes after addition was complete, the resulting reaction mass was cooled to about 6° C. and 30.0 ml (482 moles) of methyl iodide was added quickly with stirring. The temperature of the reaction mixture rose to about 20° C. The reaction mass was stirred for an additional 30 minutes in an ice bath and for about two hours at ambient temperature. The reaction mixture was poured into about 7 liters of ice water. The yellow precipitate which formed was collected, washed with water, and dissolved in about 1 liter of diethyl ether. The ether solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo on a rotary evaporator. The title compound was left as a viscous yellow-orange oil which solidified on triturating with 100 ml of hexane. The resulting yellow product had a melting point of 100° to 102° C. Elemental analysis was used to confirm the structure.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:25])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cn1ccnn1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was added dropwise to a solution of 73.1 (1.29 g, 15.5 mmol) in THF (75 mL) at −40° C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehyde was added at −40° C., and the reaction was warmed to room temperature. The reaction was quenched saturated NH4Cl (aq) after 3 hours of stirring and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 73.2 was used in the next reaction without further purification. MS ESI (pos.) m/e 296.2 (M+H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
EX-41A) To a solution of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrobenzene (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxide was added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, quenched with water, and extracted with diethyl ether. The organic layers were combined, washed with 0.1 N HCl and water, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzene product as a yellow oil. 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: CC(C)(C)c1cc(I)ccc1N=C1NCC2(CCCC2)S1
Product: CC(C)(C)c1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-tert-Butylaniline was converted to 4-iodo-2-tert-butylaniline according to Method A5a. The aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH:28]=[CH:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1=CCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide and 2,5-dihydropyrrole, TBTU, and triethylamine in DMSO.
Reaction SMILES: O.NN.[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)[CH2:5][CH3:6]>CCO>[CH2:4]([O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)[CH2:5][CH3:6]
Reactant: CCCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCO[C@H]1CC[C@H](N)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Hydrazine hydrate (1.76 g, 55 mmol) was added to a solution of trans-2-(4-propyloxycyclohexyl)-isoindole-1,3-dione (7.90 g, 27.5 mmol) in absolute EtOH (100 mL). The reaction was stirred at 50° C. for 3 h before the reaction mixture was filtered. The solvent was removed in vacuo and Et2O (250 mL) was added after stirring for 30 min the solid was filtered off and the filtrate was added 150 mL 1N HCl, the phases were separated and the aqueous phase was washed with Et2O (150 mL) before 10 N NaOH was added (until pH=11-12). The aqueous phase was extracted with EtOAc (200 mL+2×100 mL) and the organic fractions were collected and dried (MgSO4) to give 3.11 g (72%) of trans-4-propoxy-cyclohexylamine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:15]([CH2:23][CH2:24][OH:25])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[C:6]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH:15]([CH2:23][CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Yield: 95.8 %

Procedure:
Methanesulfonyl chloride (64 μL, 0.83 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (368 mg, 0.751 mmol) and triethylamine (15.4 mg, 209 μL, 1.52 mmol) in dichloromethane (2 mL) at room temperature under nitrogen. After stirring at room temperature for 1 h the crude mixture was partitioned between saturated aqueous citric acid solution (20 mL) and dichloromethane (20 mL). The phases were separated and the organic layer was evaporated to give the title compound (409 mg, 79%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.08 min; z/e 586, calcd (M+1) 586. 1H NMR (400 MHz: CDCl3): 7.50 (6H), 7.25 (4H), 7.15 (1H), 6.90 (2H), 4.50 (2H), 4.25 (2H), 3.80 (3H), 3.75 (1H), 2.95 (3H), 2.90-2.50 (3H), 2.05 (2H), 1.95-1.65 (2H), 1.55-1.35 (9H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 455 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 2.00 (m, 2 H), 2.70 (t, J=7.64 Hz, 2 H), 2.94 (t, J=7.64 Hz, 2 H), 3.05 (m, 2 H), 3.53 (m, 2 H), 3.71 (q, J=5.82 Hz, 2 H), 4.68 (t, J=6.24 Hz, 2 H), 6.95 (m, 4 H), 7.09 (m, 2 H), 7.29 (m, 2 H), 7.36 (m, 2 H), 7.70 (m, 1 H), 8.08 (s, 1 H), 8.28 (s, 1 H), 9.62 (br s, N H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[ClH:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[NH:36][CH2:35][CH2:34][CH2:33]2.C([BH3-])#N.[Na+]>C(O)(C)C>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:18]#[N:19])[CH2:16][CH2:15][CH:14]([N:36]3[C:37]4[C:32](=[CH:31][C:30]([O:29][CH3:28])=[C:39]([O:40][CH3:41])[CH:38]=4)[CH2:33][CH2:34][CH2:35]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Reactant: COc1cc2c(cc1OC)NCCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#N)CCC(N3CCCc4cc(OC)c(OC)cc43)CC2)cc1OC

Procedure:
A solution of 4-(3,4-dimethoxyphenyl)-4-cyanocyclohexanone (3.5 mmol), triethylamine (3.5 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroquinoline hydrochloride (3.5 mmol) and sodium cyanoborohydride (5 mmol) in 50 ml iso-propanol was stirred at 25° C. for several days, poured onto ice water and extracted with ethyl acetate. The salt was prepared from anhydrous HCl in ethyl acetate. ##STR15##
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCC1.[N+](C1CCCCC1)([O-])=O.[C:37]1(=[O:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(O)(=O)C.C1CCCCC1>[C:4]([O:43][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)(=[O:3])[CH3:5]
Reactant: CC(C)(C)ON=O
Reactant: O=C1CCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCC1
Agent: ON=C1CCCCC1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC(=O)OC1CCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclohexane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclohexanone oxime, nitrocyclohexane, cyclohexanone, and cyclohexyl acetate were formed in yields of 16%, 10%, 3%, and 2%, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][CH3:9])=[CH2:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6]/[CH:7]=[CH:8]\[CH3:9])=[CH2:4]
Reactant: C=C(OC)C(CC#CC)C(C)=O
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C=C(OC)C(C/C=C\C)C(C)=O

Procedure:
A mixture of 9.96 g. (60 mmol.) of 2-methoxy-3-acetyl-1-hepten-5-yne, 0.50 g. of Lindlar catalyst, and 10 drops of synthetic quinoline in 100 ml. of ethyl acetate was stirred under one atmosphere of hydrogen until hydrogen absorption was complete, then filtered, concentrated and distilled to afford (Z)-2-methoxy-3-acetyl-1,5-heptadiene; b.p. 64°-66°, (2.0 mmHg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCC(=O)OC(C)(C)C)c2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of methyl 6-(3′-hydroxyphenyl)-pyridine-2-carboxylate (7) (600 mg, 2.6 mmol, 1 eq.) and t-butyl 6-bromohexanoate (980 mg, 3.9 mmol, 1.5 eq.) in DMF (7 mL) was added K2CO3 (1.08 g, 7.8 mmol, 3 eq.). The mixture was stirred vigorously overnight at 60° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica using ethyl acetate:hexanes eluant to provide 730 mg of 8. Yield 73%. MS m/z 400 [M+H]+
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35](O)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]>ClCCl>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]([C:16]1[C:15]2[C:19](=[C:20]([CH2:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)[CH:36]1[CH2:38][CH:37]1[C:39]#[N:40]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
96.9 mg (0.44 mmol) of indium(III) chloride and 0.06 ml (0.72 mmol) of trifluoroacetic acid were added to 113 mg (0.40 mmol) of the compound from Example 87A with a purity of 80% and 100 mg (0.48 mmol) of the compound from Example 162A under argon in 4 ml of dichloromethane, and the mixture was heated under reflux for 1 h. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 69.0 mg (41% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([S:19][CH3:20])[N:13]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:18][C:16]1[N:15]=[C:14]([S:19][CH3:20])[N:13]=[C:12]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(Nc2ccc(C(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaHMDS (41 mL, 1M in THF) was added into the solution of 4,6-dichloro-2-(methylthio)pyrimidine (4 g) and tert-butyl 4-aminobenzoate (3.96 g) in THF (200 mL). The reaction was stirred at room temperature for 16 hours, before being quenched by water (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL)). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give tert-butyl 4-(6-chloro-2-(methylthio)pyrimidin-4-ylamino)benzoate which will be used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:40][C:41]1[C:42]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:43]=2[S:44][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:46]([C:45]2[S:44][C:43]3[CH:49]=[CH:50][CH:51]=[C:52]([F:53])[C:42]=3[C:41]=2[Cl:40])=[O:47])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N3 is prepared according to a method similar to Method D. [4-(2-methoxy-5-pyridin-3-yl-benzylamino)-cyclohexyl]-carbamic acid tert-butyl ester (N2) (1.035 g, 2.52 mmol) is dissolved in 10 mL anhydrous methylene chloride. N,N-Diisopropylethylamine (0.526 mL, 3.02 mmol) is added followed by 3-chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride (6) (0.690 g, 2.77 mmol). The mixture is allowed to stir overnight at room temperature and then is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and evaporated, and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. {4-[(3-Chloro-4-fluoro-benzo[b]thiophene-2-carbonyl)-(2-methoxy-5-pyridin-3-yl-benzyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (N3) is obtained (0.93 g, 1.48 mmol; 59% yield).