Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:25].[I-].N.CCO>>[NH2:25][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3cccs3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccs3)Oc3ccc(Br)cc32)N=C1N
Yield: 27.1 %

Procedure:
A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH4I (13.7 mg, 0.094 mmol) in a solution of NH3/EtOH (2 mL, 2 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuum to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-1′-methyl-2-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 20%). 1H-NMR (CDCl3): 2.52 (m, 2H), 3.14 (s, 3H), 6.12 (d, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.14 (d, 1H), 7.43 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15]C)[C:5]([O:13]C)=[C:6]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([OH:13])=[C:6]([C:8]2[NH:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1
Reactant: COc1cc(Cl)cc(-c2cnc[nH]2)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Cl)cc(-c2cnc[nH]2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a suspension of 5-(5-chloro-2,3-dimethoxyphenyl)-1H-imidazole (0.080 g, 0.335 mmol) in dichloromethane (4 mL) at −78° C. was added BBr3 (1.01 mmol) and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction was quenched by cautious addition of satd. NH4Cl solution (3 mL). The product was extracted with CH2Cl2 (3×10 mL), the combined organic extract was washed with water, brine and dried (MgSO4) and concentrated in vacuum to afford the crude product. The crude was passed through a short pad of silica gel to afford the final product. Yield 62%. 1H NMR: 6.82 (d, 1H, J=2.40 Hz), 6.99 (d, 1H, J=2.40 Hz), 7.34 (s, 1H), 7.75 (s, 1H)
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=O)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:67][C:68]([CH3:88])=[CH:69][CH2:70][CH2:71]/[C:72](/[CH3:87])=[CH:73]/[CH2:74][CH2:75]/[C:76](/[CH3:86])=[CH:77]/[CH2:78][S:79][CH2:80][C@H:81]([NH2:85])[C:82]([OH:84])=[O:83].[OH-].[Na+]>C1COCC1.CO>[C:20]([O:19][C:17]([NH:16][C@H:12]([C:13]([NH:85][C@H:81]([C:82]([OH:84])=[O:83])[CH2:80][S:79][CH2:78]/[CH:77]=[C:76](\[CH3:86])/[CH2:75][CH2:74]/[CH:73]=[C:72](\[CH3:87])/[CH2:71][CH2:70][CH:69]=[C:68]([CH3:88])[CH3:67])=[O:15])[CH2:11][CH2:10][C:9]([OH:8])=[O:24])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 100 mL round bottom flask, to a solution of (S)-5-(benzyloxy)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (674 mg, 2 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 1040 mg, 2 mmol) and in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (1.04 mL, 6 mmol) dropwise. After 10 min, S-trans, trans-farnesyl-L-cysteine (650 mg, 2 mmol) was added slowly. The solution was stirred at room temperature for 4 h. The reaction was quenched by 1 N HCl and pH of the solution was adjusted to 3.0. The mixture was extracted by ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo. Half of the residue was used directly for next step to afford crude Compound N-66. To this crude Compound N-66 obtained above dissolved in MeOH (1 mL), was added 5 N NaOH (2 mL, 10 mmol). The reaction was left at room temperature for 10 min. The reaction was quenched by 1 N HCl and pH of the solution was adjusted to 2.0. The mixture was extracted by ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was then further purified by preparative HPLC (164 mg, 30%) to yield Compound N-66. 1H-NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 1.62 (s, 6H), 1.68 (s, 3H), 1.70 (s, 3H), 1.95-2.09 (m, 10H), 2.46-2.54 (m, 2H), 2.91 (dd, J=5.0, 15.0 Hz, 1H), 3.04 (dd, J=5.0, 15.0 Hz, 1H), 3.17-3.25 (m, 2H), 4.56 (dd, J=10.0, 15.0 Hz, 1H), 4.77-4.81 (m, 1H), 5.12 (m, 2H), 5.23 (t, J=10.0 Hz, 1H), 5.64 (d, J=10.0 Hz, 1H), 7.66 (d, J=10.0 Hz, 1H), 8.40 (broad, 2H). 13C-NMR (125 MHz, CDCl3): δ 16.06, 16.15, 17.75, 25.77, 26.52, 26.74, 28.01, 28.33, 29.73, 29.89, 32.60, 39.70, 39.74, 52.22, 52.95, 80.91, 119.57, 123.83, 124.35, 131.38, 135.34, 140.04, 156.06, 172.18, 174.00, 177.16; ES-MS: mass calcd for Chemical Formula: C28H46N2O2S 554.74. Found (M+Na) m/z 577.4.
Reaction SMILES: CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:22][O:23][C:24]1[C:29]([C:30]2[C:34]3[N:35]=[C:36](S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([O:45][CH3:46])=[O:44])=[CH:28][CH:27]=[C:26]([CH3:47])[N:25]=1.[CH3:48][C:49]1[C:50]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)=[CH:51][C:52]([O:58][CH:59]([CH3:61])[CH3:60])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1>CN(C=O)C>[CH:56]([N:55]([C:53]1[CH:54]=[C:49]([CH3:48])[C:50]([N:62]2[CH2:63][CH2:64][N:65]([CH3:68])[CH2:66][CH2:67]2)=[CH:51][C:52]=1[O:58][CH:59]([CH3:61])[CH3:60])[C:36]1[N:37]=[CH:38][C:33]2[S:32][C:31]([C:43]([O:45][CH3:46])=[O:44])=[C:30]([C:29]3[C:24]([O:23][CH3:22])=[N:25][C:26]([CH3:47])=[CH:27][CH:28]=3)[C:34]=2[N:35]=1)=[O:57]
Reactant: Cc1cc(NC=O)c(OC(C)C)cc1N1CCN(C)CC1
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccc(C)nc1OC
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3cc(C)c(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccc(C)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
0.7 ml of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) is added to a mixture of 300 mg of methyl 7-(2-methoxy-6-methylpyridin-3-yl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate and 231 mg of N-[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 8 ml of anhydrous DMF. The mixture is stirred at ambient temperature for 16 h, and then evaporated under vacuum at a temperature of 55° C., and the residue is diluted with ethyl acetate and water. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 25 g of silica, elution being carried out with 50-100% of acetone in dichloromethane so as to obtain 422 mg of methyl 2-{formyl[5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxy-6-methylpyridin-3-yl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of an orangey-coloured solid.
Reaction SMILES: N([O-])=O.[Na+].[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[N-:20]=[N+:21]=[N-].[Na+].C(=O)(O)[O-].[Na+]>O.Cl>[N:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(C=Cc2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=Cc2ccncc2)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of sodium nitrite (1.76 g, 25.5 mmol) in 10 mL water was added dropwise to a solution of 4-(2-pyridin-4-yl-vinyl)-phenylamine (2.0 g, 10.2 mmol) in 102 mL 4M HCl at 2-3° C. After stirring the mixture at this temperature for 1 hr, a solution of sodium azide (1.32 g, 20.4 mmol) in 10 mL water was slowly added dropwise, maintaining the temperature at 2-3° C. Stirring was continued for 30 min at this temperature and then the ice bath was allowed to come to ambient temperature while stirring continued overnight Saturated aqueous sodium bicarbonate was added carefully to this mixture with stirring until the evolution of gas subsided. The precipitate was filtered off and dried overnight in the funnel to yield 1.875 g of the product as a beige powder (83% yield), mp 88.2-89.4° C. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=1.4, 6.1 Hz, 2H), 7.46 (ddd, J=1.9, 21, 8.5 Hz, 2H), 7.29 (dd, J=1.4, 6.1 Hz, 2H), 7.18 (d, J=16.4 Hz, 1H), 6.98 (ddd, J=2.0, 2.7, 8.5 Hz, 2H), 8.90 (d, J=16.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 150.3, 144.4, 140.3, 133.1, 132.0, 128.4, 125.7, 120.8, 119.5. λmaxCH3CN 323 nm (ε 3.92×104). IR νmax (cm−1) 2122 (N3).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:1]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: 25 °C

Procedure:
To a flask containing methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (100 mg, 0.581 mmol) in CH2Cl2 (5.8 mL) at 0° C., was added Dess-Martin periodinane (493 mg, 1.16 mmol). The reaction was allowed to warm to room temperature over an hour and then was diluted with EtOAc (60 mL), washed with saturated K2CO3 solution (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded methyl trans-4-formylcyclohexanecarboxylate. Rf=0.87 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 9.63 (s, 1H), 3.67 (s, 3H), 2.51-2.05 (m, 6H), 1.63-1.26 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.O[CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:33][CH:32]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1.[CH2:48]([NH:50][CH2:51][CH2:52][OH:53])[CH3:49]>C(Cl)Cl>[CH2:48]([N:50]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:35][CH:36]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1)[CH2:51][CH2:52][OH:53])[CH3:49]
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(CO)ccc4c23)cc1)c1ccccc1
Reactant: CCNCCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO)Cc1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
DIEA (0.03 mL, 0.19 mmol) and methanesulfonyl chloride (0.01 mL, 0.09 mmol) were added to a solution of 273 (27 mg, 0.06 mmol) in CH2Cl2 and stirred for 2 h at room temperature. 2-(Ethylamino)ethanol (17 mg, 0.19 mmol) was added, and the reaction mixture was stirred for 1 h. The crude product was purified directly via HP-LC to provide 274 (6 mg, 16% yield) as a solid. LC-MS (M+H=508, obsd.=508).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a suspension of 5.7 g (20.0 mmol) 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester in 120 mL tetrahydrofuran, 3.44 g (24.0 mmol) isopropyl-piperidin-4-ol and 6.30 g (24.0 mmol) triphenylphosphine were added. The suspension was cooled to 0° C. and 5.53 g (24.0 mmol) di-tert-butyl azodicarboxylate was added. The ice bath was removed and the reaction mixture was stirred for 18 h at room temperature. The volatile components were removed and the residue was chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to afford 6.2 g (76%) of the compound as a light-yellow foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)=O)C.[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>ClCCl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:8]2[S:7][C:6]([C:4]([NH:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:3])=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:24][CH:23]=1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 50 °C
Yield: 29 %

Procedure:
Part D; Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.00 gram, 2.42 mmol) is added to 1-aminopiperidine (10 mL) and the resulting stirred mixture is heated at 50° C. for 4 hours. Dichloromethane is added and the resulting solution is washed twice with water, dried over MgSO4, filtered and most of the dichloromethane is removed by evaporation in vacuo. Diisopropyl ether is added and the formed precipitate is removed by filtration. The filtrate is concentrated in vacuo and purified by flash chromatography (ethyl acetate: petroleum ether (40-60)=1:3 (v/v)) to produce 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(1-piperidinyl)thiazole-2-carboxamide (330 mg, 29% yield) as a white foam. 1H-NMR (400 MHz, CDCl3): δ 7.92 (s, 1H), 7.47 (t, J=2 Hz, 1H), 7.24-7.32 (m, 4H), 7.13 (dt, J=8 Hz, J=2 Hz, 2H), 2.85-2.93 (m, 4H), 1.40-1.82 (m, 6H).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Solvent: CCO
Product: COc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)cc1

Procedure:
A mixture of (1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.027 g, 0.10 mmol) and p-methoxybenzylamine (0.28 g, 2.03 mmol) in ethanol (1 ml) was refluxed under N2 overnight. The solvent was removed and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate/Et3N=6:4:0.2) to give (2S, 4R, 5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol, (−)-29a, 0.03 g (73.2%, [α]D=(−)71.9, c=1, MeOH).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:25])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)[CH3:2]>C1COCC1.[Pt](=O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]2[C:9]3[C:4](=[C:3]([CH2:1][CH3:2])[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:25])=[CH:21][CH:20]=1
Reactant: CCc1cc2c(ccc(=O)n2Cc2ccc([N+](=O)[O-])cc2)c(CC)n1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(N)cc2)c(CC)n1

Procedure:
A solution of compound B (16.0 g) in THF (200 ml) was cataltically hydrogenated over platinum (IV) oxide (320 mg) at one atmosphere for 3 hours. The catalyst was removed by filtration and the solvent was removed by evaporation to give 1-(4-aminobenzyl)-5,7-diethyl-1,6-naphthyridin-2(1H)-one (C) as an off white solid (14.5 g), m.p. 164°-165° C.; NMR (d6 -DMSO): 1.85(t, 3H), 1.2(t, 3H), 2.72(q, 2H), 3.03(q, 2H), 5.1(s, 2H), 5.28(s, 2H), 6.48(d, 2H), 6.66(d, 1H), 6.94(d, 2H), 7.14(s, 1H), 8.16(d, 1H); mass spectrum (+ve FAB, MeOH/DMSO/NBA): 308 (M+H)+ ; microanalysis, found: C, 74.0; H, 6.9; N, 13.1%; C19H21N3O requires C, 74.2; H, 6.9; N, 13.1 %.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH2:25][CH2:26][CH2:27][OH:28]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:25][CH2:26][CH2:27][OH:28])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: NCCO
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(NCCO)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 2-amino-ethanol. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (t, J=5.81 Hz, 1H), 7.59 (d, J=9.21 Hz, 1H), 7.47 (s, 2H), 7.27 (t, J=5.21 Hz, 1H), 6.87 (d, J=9.21 Hz, 1H), 4.79-4.81 (m, 1H), 3.55-3.59 (m, 2H), 3.44-3.48 (m, 2H), 3.22-3.23 (m, 2H), 1.98-2.03 (m, 2H), 1.73-1.85 (m, 5H), 1.22-1.31 (m, 2H). m/z: 398.3 [M+H]+
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[C:37]=1[CH3:43])C1C=CC=CC=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:42][C:38]3[C:37]([CH3:43])=[C:36]([CH:41]=[CH:40][CH:39]=3)[C:35]([OH:44])=[O:34])=[O:26])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1c(N)cccc1C(=O)OCc1ccccc1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: Cc1c(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cccc1C(=O)O

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 3-amino-2-methyl-benzoic acid benzyl ester (prepared in two steps from 2-methyl-3-nitro-benzoic acid) according to the procedure of Example 20, step d. The benzyl ester was hydrogenated using the same procedure as in Example 1, step c to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 13.00 (1H, br s), 11.95 (1H, br s), 9.31 (1H, br s), 8.01 (1H, d), 7.49 (1H, d), 7.24 (1H, m), 2.85 (2H, m), 2.60 (1H, m), 2.39 (3H, s), 1.93-1.24 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.84; H, 8.55; N, 7.80%. C37H56N4O8.1.0 mol H2O requires: C, 63.23; H, 8.32; N, 7.97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)c1
Product: CC(=O)Nc1cccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)c1
Reaction time: 8 h

Procedure:
The resulting ethereal solution from Example 4 containing 1-[4-(4-chlorophenyl)-2-(3-aminophenylthio)-n-butyl]imidazole was treated at room temperature with stirring with acetic anhydride (1.5 m.). After stirring overnight, the mixture was evaporated to dryness in vacuo and the residue chromatographed on silica gel eluting with methylene chloride followed by 2.2% water in ethyl acetate. The resulting pure product, 1-[4-(4-chlorophenyl)-2-(3-acetylaminophenylthio)-n-butyl]imidazole, obtained as a gum, was dissolved in a small volume of methanol and treated with excess ethereal hydrogen chloride. The solution was filtered, evaporated almost to dryness and evacuated in a warm water bath to give 1-[4-(4-chlorophenyl)-2-(3-acetylaminophenylthio)-n-butyl]imidazole hydrochloride 1.79 g as a brittle foam, dec 87°-92° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29](O)=O)=[CH:20]1.C(N(C(C)C)CC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:29][CH2:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(OCC2CCCN(CCc3c[nH]c4ccccc34)C2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
3-(4-Trifluoromethyl-phenoxymethyl)-piperidine (50 mg, 0.19 mmol), (1H-Indol-3-yl)-acetic acid (73 mg, 0.21 mmol), the amide coupling agent BrOP (123 mg, 0.32 mmol), and diisopropylethylamine (75 mg, 0.58 mmol) were dissolved in 2 mL of anhydrous dichloromethane. The mixture was kept at room temperature overnight, diluted with 10 mL of water, and 10 mL of ether. Extractive workup gave in each case, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate (71 mg, 90%). This amide was dissolved in 5 mL of THF at 0° C. and excess lithium aluminum hydride (50 mg, ca. 8 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 53 mg of 3-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indole, 180, was obtained (77%). Data for this compound: MS 403 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:25][N:26]([CH3:33])[CH2:27][CH:28]=[CH:29][C:30](Cl)=[O:31]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH:3]=[CH:4][C:5]=3[CH3:24])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: CN(C)CC=CC(=O)Cl
Product: Cc1ccc(NC(=O)/C=C/CN(C)C)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl) pyrimidine-4,6-diamine (Int-F) and 4-dimethylamino-2-butenoyl chloride were combined in a manner similar to that described in Scheme 4a to give (E)-N-[3-(6-{3-chloro-4-fluorophenyl}amino-pyrimidin-4-ylamino)-4-methylphenyl]-4-(dimethylamino)but-2-enamide (I-54). MS (m/z): 455/457 (M+1, 100/39%). 1H NMR (DMSO-d6) δ 11.02 (bs, 1H), 10.66 (bs, 1H), 9.92 (bs, 1H), 9.39 (bs, 1H), 7.92-7.94 (m, 1H), 7.75 (bs, 1H), 7.27-7.56 (m, 4H), 6.80 (m, 1H), 6.54 (d, 1H), 5.89 (bs, 1H), 3.92 (bs, 2H), 2.75 (bs, 6H), 2.17 (bs, 3H).