Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[OH:37][CH2:36][CH2:38][NH:39][C:3](=[O:4])[C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:31])([F:33])[F:32])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:1]
Reactant: NCCO
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Product: CC(C)(C(=O)NCCO)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 453, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ethanolamine to give 324. MS(ESI+) 548.1. 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.30-8.25 (m, 2H), 8.07 (s, 1H), 7.52 (dd, J=8.3, 1.5, 1H), 7.41 (d, J=1.5, 1H), 7.20 (t, J=5.4, 1H), 5.86 (q, J=8.7, 2H), 4.59 (t, J=5.4, 1H), 4.40 (t, J=4.8, 2H), 3.47 (t, J=4.9, 2H), 3.36 (q, J=6.0, 2H), 3.12 (q, J=6.0, 2H), 1.75 (s, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]([NH:17][NH2:18])=[O:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(OC)(OC)C(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:16][C:2]([CH:1]([CH3:4])[CH3:3])=[N:18][N:17]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)NN)CC1
Agent: COC(OC)(OC)C(C)C
Product: CC(C)c1nnc(C2(C)CCN(C(=O)OC(C)(C)C)CC2)o1
Yield: 105.3 %

Procedure:
30 g 4-hydrazinocarbonyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester was refluxed with 150 mL 1,1,1-trimethoxy-2-methyl-propane overnight. The excess of reagent was removed under vacuum and the residue was purified by chromatography on silica gel to give 19 g of the desired product.
Reaction SMILES: NC1N=[C:6](N2CCC3(CN[C@H](C(OC(C)C)=O)C3)CC2)[CH:5]=[C:4](O[C@H](C2C=CC(C3C=CC(C)=C(C)C=3)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([OH:67])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([C:82]3[CH:87]=[CH:86][C:85]([O:88][CH:89]([CH3:91])[CH3:90])=[CH:84][CH:83]=3)=[CH:78][C:77]=2[N:92]2[CH:96]=[CH:95][C:94]([CH3:97])=[N:93]2)[C:72]([F:75])([F:74])[F:73])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([O:67][CH:5]([CH3:6])[CH3:4])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([C:82]3[CH:87]=[CH:86][C:85]([O:88][CH:89]([CH3:91])[CH3:90])=[CH:84][CH:83]=3)=[CH:78][C:77]=2[N:92]2[CH:96]=[CH:95][C:94]([CH3:97])=[N:93]2)[C:72]([F:73])([F:74])[F:75])[N:52]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Reactant: Cc1ccn(-c2cc(-c3ccc(OC(C)C)cc3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Cc1ccn(-c2cc(-c3ccc(OC(C)C)cc3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 11).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH2:10][C:11]1[C:19]([C:20](=[O:23])[NH:21][CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.O>CC(N(C)C)=O>[CH3:22][N:21]1[C:20](=[O:23])[C:19]2[C:11](=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][CH:18]=2)[N:10]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CNC(=O)c1cccc(C(=O)O)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 85.9 %

Procedure:
Sodium metabisulfite (3.56 g, 18.7 mmol) was added to a solution of 2-amino-3-(methylcarbamoyl)benzoic acid 31 (2.80 g, 14.4 mmol) and 3-(trifluoromethyl)benzaldehyde 32 (2.51 g, 14.4 mmol) in DMAC (45 mL). The reaction mixture was stirred at 100° C. for 21 h. H2O (150 mL) was added and the resulting precipitate was collected by filtration, rinsed with H2O and dried to give 33 (4.31 g, 84% yield).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[S:9][CH:10]=[CH:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.72 (s, 2H) 7.41 (s, 4H) 7.56 (dd, J=4.42, 2.59 Hz, 4H) 7.63-7.80 (m, 2H) 8.36 (d, J=5.19 Hz, 1H) 11.81 (s, 1H); MS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]([OH:22])[CH2:23][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 120 h
Yield: 84.2 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline (96 mg, 0.261 mmol) in tetrahydrofuran (2.6 ml) under a nitrogen atmosphere, diethylamine (0.5 ml) was added and the mixture was stirred at 50° C. for 5 days. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (96.9 mg, 0.220 mmol, 84.2%) as light yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][CH:17]2[CH2:19][CH2:18]2)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1NC1CC1
Reaction time: 6 h

Procedure:
1-Benzyl-3,3-dimethyl-4-piperidone (10.0 g, 46.0 mmol), was added to the stirred solution cyclopropylamine (13.1 g, 230.0 mmol) in methanol (150 ml) and stirred for 6 hr. Sodium cyanoborohydride (2.9 g, 46.0 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated. The obtained crude product was purified over silica gel column. Eluted from 5% ethyl acetate in hexane gave 1-benzyl-4-cyclopropylamino-3,3-dimethyl piperidine. Yield 8.0 g (67.3%), C17H26N2, m/z 259 (M+1), PMR (CDCl3): 0.4 (m, 2H), 0.82 (s, 3H), 1.06 (s, 3H), 1.16 (m, 2H), 1.5 (bs, 1H, D2O exchangeable), 1.7 (m, 2H), 1.9-2.95 (m, 5H), 3.3-3.6 (m, 3H), 7.22 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[C:15]([CH3:31])=[N:16][C:17]([N:20]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:29][CH2:28][CH2:27][C@@H:26]4[CH3:30])[CH2:21]3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH3:31][C:15]1[C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[C:3]2=[O:2])=[CH:19][CH:18]=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])[CH2:21]2)[N:16]=1
Reactant: COC(=O)C1(CCNc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCOCC2)C1=O
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a solution of 4-{2-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (0.034 g, 0.079 mmol) in THF (10 mL) was added a solution of potassium t-butoxide (1M in THF) (0.2 mL), and allowed to stir at room temperature. After 3 hours additional potassium t-butoxide (0.4 mL) was added and reaction mixture stirred at room temperature for 16 hours. More potassium t-butoxide (0.2 mL) was added and stirred at room temperature for 4 hours, then heated to 50° C. for 3 hours. Reaction mixture was cooled to room temperature then diluted with ethyl acetate (10 mL), quenched with brine (2 mL). Aqueous layer was extracted with ethyl acetate (2×10 mL). Combined organics were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification over silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.0068 g (22%) of title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N-].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:17]=1>C1(C)C=CC=CC=1.[Cu]>[C:7]([O:6][C:4]([CH2:3][C:18]1[N:16]2[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][C:15]2=[N:20][C:19]=1[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccc(-c2cn3cc(C)ccc3n2)cc1
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc3ccc(C)cn3c2CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Tert-butyl diazoacetate (5 ml, 35.15 mmol) then copper powder (2.5 g) were gradually added to a refluxing solution of 9 (5.0 g, 18.8 mmol) in anhydrous toluene (150 ml). After a further 3 h of reflux, the mixture was cooled to room temperature, the suspension filtered and dried. Purification by column chromatography on silica gel (ethyl acetate-hexane, 1:1) gave methyl 4-(3-tert-butoxycarbonylmethyl-6-methylimidazo[1,2-a]pyridin-2-yl)benzoate 10 (3.35 g, 47%).
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1.C([O-])(O)=O.[Na+].[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl>[N:34]([CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CO)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CCC=C(CN=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
At 0° C., triethylamine (3.7 ml, 26.2 mmol) and, dropwise, methanesulphonyl chloride (1.2 ml, 15.44 mmol) were added to a solution of tert-butyl 5-hydroxymethyl-3,6-dihydro-2H-pyridine-1-carbamate (Tetrahedron 1998, 54, 7045–7056, 2.8 g, 13.1 mmol) in DCM (50 ml). The reaction mixture was stirred at 0° C. for 20 minutes before a saturated solution of NaHCO3 (40 ml) was added, and the two phases were separated. The aqueous phase was extracted with dichloromethane (40 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over MgSO4 and concentrated. The crude product was dissolved in DMF (50 ml), and sodium azide (1.7 g, 26.1 mmol) was added. The mixture was heated to 80° C. Reaction monitored by LCMS. Once the reaction was complete, the mixture was cooled and concentrated. The residue was taken up in EtOAc and water and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 1/6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCCC3)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1

Procedure:
A solution of N-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoroacetamide (10.7 g, 31.1 mmol), N-bromosuccinimide (6.6 g, 37 mmol), and AIBN (200 mg, 1.2 mmol) in CCl4 (300 ml) was stirred at reflux under nitrogen for 1 hour. After cooling the solution was filtered, concentrated in vacuo to a volume of ~ 25 ml, and applied to a column of silica gel. Elution with ethyl acetate:hexane (1:10) gave a mixture of benzylic bromides (10.7 g). A solution of the bromides and Li2CO3 (5.0 g, 68 mmol) in DMF (50 ml) was stirred at 110-120° C. under nitrogen for 3 hours and then overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in methylene chloride (150 ml) and washed with water (50 ml). The aqueous phase was separated, extracted with more methylene chloride (100 ml), and the combined organic solutions were then washed with a small volume of water, dried (K2CO3) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:13) to give N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoroacetamide and the corresponding 5,6,-dihydroisomer in a 3:1 ratio as determined by NMR (4.3 g). 1H NMR (DMSO-d6, 200 MHz) δ: 2.10-2.46 (m, 3H, CH2), 2.63-2.89 (m, 1H, CH2), 6.03-6.22 (m, 1H, CH), 6.41 (dt, J=10,2 Hz, 0.25H, CH), 6.48 (dt, J =10,2 Hz, 0.75H, CH), 7.08-7.33 (m, 3H, Ar), 7.41 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O: C, 66.67; H, 3.83; N, 8.18. Found: C, 66.55; H, 3.86; N, 8.10.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[C:16]([Cl:22])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:21]/[C:17]1[C:18]([Cl:20])=[CH:19][C:14]([Br:13])=[CH:15][C:16]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 4-bromo-2,6-dichlorophenylamine (14.4 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol). The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound (quantitative yield). This was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:13]([O:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:16])[CH:14]=[CH2:15]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(C)cc1C(C)(C)C

Procedure:
To a 300-ml four-necked flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel were added 32.8 g (0.20 mole) of 2-tert-butyl-4-methylphenol, 22.3 g (0.22 mole) of triethylamine and 100 g of toluene, and after replacing air in the flask by nitrogen, 19.10 g (0.21 mole) of acryloyl chloride was added dropwise at a reaction temperature of 30° C. over 1 hour. After completion of the dropwise addition, excessive triethylamine was neutralized with hydrochloric acid, the reaction solution was washed with water, and toluene was then removed from the organic layer by evaporation under reduced pressure to obtain 43.0 g of a crude product (yield, 99%). This crude product was purified by distillation under reduced pressure to obtain a white and transparent 2-tert-butyl-4-methylphenol monoacrylate.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:1]([N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[C:10]1=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2ccccc2C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(=O)c2ccccc21
Temperature: 22 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
In a 250 mL flame dried round bottom flask equipped with a stir bar, tert-butyldimethylsilyl chloride (4.5 g, 30 mmol) is dissolved in 150 mL dichloromethane. To this solution, in a single portion, isatin (2.2 g, 15 mmol) and 4-dimethylaminopyridine (0.18 g, 1.5 mmol) are added. The flask is sealed with a rubber septum and purged with nitrogen. Triethylamine (6.3 mL, 45 mmol) is added in one portion through a syringe and mixture is allowed to stir for 24 h at 22° C. The volatiles are removed in vacuo and the resultant dark orange solid is purified by silica gel chromatography (hexanes to 1:1 hexanes:dichloromethane to dichloromethane) to afford an orange solid, which is recrystallized from hot EtOH (details below) to afford 14a (2.6 g, 9.9 mmol, 67% yield) as an orange crystalline solid. Please note that for long-term storage, N-tert-butyldimethylsilyl protected isatins should be kept under an inert atmosphere at −15° C. 1-(tert-Butyldimethylsilyl)indoline-2,3-dione (14a): M.p.=123-124° C. IR (neat): 2929 (w), 2853 (w), 1731 (s), 1603 (m), 1589 (m), 1463 (m), 1325 (m), 1252 (m), 1170 (m), 1139 (m), 927 (m), 835 (s), 796 (m), 752 (s), 686 (m), 466 (m), 424 (m) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.63-7.61 (1H, m), 7.53-7.49 (1H, m), 7.10-7.03 (2H, m), 1.02 (9H, s), 0.56 (6H, s); 13C NMR (100 MHz, CDCl3): δ 184.2, 164.9, 155.4, 138.3, 125.6, 123.4, 120.0, 115.1, 26.4, 19.7, −3.3; HRMS Calcd for C14H20NO2Si [M+H]+: 262.12633. Found: 262.12608.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[N:46]1([CH:52]2[CH2:57][CH2:56][N:55]([C:58](=[O:60])[CH3:59])[CH2:54][CH2:53]2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:58]([N:55]1[CH2:54][CH2:53][CH:52]([N:46]2[CH2:47][CH2:48][N:49]([C:21]([N:11]3[C@@:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH3:13])[C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH3:38])[N:9]=[C:10]3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:32])([CH3:31])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[O:22])[CH2:50][CH2:51]2)[CH2:57][CH2:56]1)(=[O:60])[CH3:59]
Reactant: CC(=O)N1CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCN(C(C)=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(4-piperazin-1-yl-piperidin-1-yl)-ethanone trifluoroacetate to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 743.4 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:12][C:10]2[S:11][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:9]=2)=[O:30])=[CH:27][CH:26]=1)#[N:24]
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccc(F)cc2)cc1
Yield: 85.9 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-fluoro-benzyl)-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 13 and p-cyanobenzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography, and recrystallized with petroleum ether and ethyl acetate to obtain a product as a white solid in a yield of 85.9%, mp: 191-192 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.79 (3H, s, OCH3), 4.18 (2H, s, CH2), 6.73 (2H, d, J=8.96 Hz, ArH), 7.03 (2H, t, 3JFH=3JHH=8.68 Hz, ArH), 7.19 (2H, dd, 3JHH=8.96, 4JFH=5.60 Hz, ArH), 7.24 (2H, d, J=8.96 Hz, ArH), 7.53 (2H, d, J=8.40 Hz, ArH), 7.76 (2H, d, J=8.40 Hz, ArH), 11.74 (1H, br, CONH); EI-MS m/e (%): 443.1 (M, 100), 130.0 (48); HREI-MS Calcd. for C25H18FN3O2S: 443.1104. found: 443.1108. Anal. Calcd. for C25H18FN3O2S: C, 67.71; H, 4.09; N, 9.47. found: C, 67.89; H, 3.97; N, 9.42.