Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[CH3:15][C:16]([Si:19]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a stirring solution of 2-iodobenzylalcohol (2.34 g, 10 mmol) in 50 mL DMF was added imidazole (1.02 g, 15 mmol, 1.5 equiv) and TBSCl (1.66 g, 11 mmol, 1.1 equiv). The mixture was stirred at room temperature for 5 h, then 40 mL of water was added. The mixture was transferred to a separatory funnel. The aqueous layer was separated and extracted with ether (2×40 mL). The combined organic layers were then washed with water (2×40 mL), dried with MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography and then Kugelrohr distillation to afford the product (3.107 g, 89%) as a clear colorless liquid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH:16]([C:25]([O:27]C)=[O:26])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1.CO.O.[OH-].[Li+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH:16]([C:25]([OH:27])=[O:26])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Oc1ccccc1-3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Oc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Dimethyl 13-cyclohexyl-6,7-dihydroindolo[1,2-d][1,4]benzoxazepine-6,10-dicarboxylate was dissolved in THF:MeOH (1:1) (0.02 M) and to that solution 1.4 eq. of an aq. solution of lithium hydroxide monohydrate (0.1 N) were added. The solution was stirred at RT for 2 h. Volatiles were reduced in vacuo, the residue acidified with 1N HCl (aq) and the resultant precipitate filtered and dried in vacuo to afford the title compound (99%). (ES+) m/z 420 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1([C:12]2[C:7]3[C:6](=[CH:5][C:4]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CCC2)cc1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1-c1ccccc1)CCN=C2C1(c2ccccc2Cl)CCC1

Procedure:
A mixture of N-[2-(2-methoxy-5-biphenylyl)ethyl]-1-(2-chlorophenyl)cyclobutane carboxamide (12.5 g, prepared as described in Example E30), phosphorus oxychloride (25 ml) and acetonitrile (150 ml) was heated under reflux for 6 hours. The solvent was removed by distillation and the residue added to a mixture of ice and water. The mixture was extracted with dichloromethane to yield a solid which was recrystallised from propan-2-ol to give 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-6-phenyl-3,4-dihydroisoquinoline, m.p. 149°-152° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Product: Cc1cccc([N+](=O)[O-])c1N1CCCCC1
Yield: 35 %

Procedure:
Using a procedure similar to Example 8, step (a), 2-chloro-3-methylnitrobenzene (264 mg, 1.53 mmol) was heated to 110° C. overnight in 3 mL of piperidine to afford 128 mg (35%) of the title compound and an undetermined amount of starting material. 1H-NMR (CDCl3; 400 MHz): δ 7.41-7.34 (m, 2H), 7.02 (t, 1H, J=7.7 Hz), 2.96-2.93 (m, 4H), 2.36 (s, 3H), 1.65 (br s, 6H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.BrCCCCCCCCCCCCCCC[CH2:27][CH2:28][CH3:29].[Al+3].[Cl-].[Cl-].[Cl-].[C:34](=S)=S>>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:28]([CH3:27])([CH3:29])[CH3:34]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: S=C=S
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1cc(C(C)(C)C)c(Br)o1

Procedure:
The compound was prepared according to the procedure as described in Gilman, H., et al., J. Am. Chem. Soc., 1939, Vol. 61, pp 473-478, more particular according the general procedure on page 467-477) from methyl 5-bromofuran-2-carboxylate (5.00 g, 24.4 mmol), 1-bromooctadecane (8.13 g, 24.4 mmol), and anhydrous AlCl3 (6.50 g, 48.8 mmol) in CS2 (50 mL) to yield methyl 5-bromo-4-tert-butyl-furan-2-carboxylate. 1H-NMR (400 MHz, CDCl3) δ: 7.12 (s, 1H), 3.88 (s, 3H), 1.33 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C)C=O.O>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C@:16]1([CH3:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of Example 186B (168 mg, 0.36 mmol) in 3 mL of N,N-dimethyl formamide was cooled to 0° C., treated with triethylamine (90 μL, 0.82 mmol) and methanesulfonyl chloride (32 μL, 0.41 mmol), allowed to warm to room temp, stirred for 2 h, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water and concentrated in vacuo to afford a yellow foam. The concentrate was purified on silica gel with a gradient of methanol in dichloromethane (0-2%) to afford the title compound (150 mg, 76% yield). 1H NMR (500 MHz, C6D6) δ ppm 0.40 (m, 1H) 0.72 (s, 9H) 0.82 (m, 1H) 1.55 (s, 3H) 2.01 (m, 1H) 2.21 (td, J=12.66, 3.97 Hz, 1H) 2.97 (s, 3H) 4.28 (d, J=5.49 Hz, 2H) 7.30 (s, 1H) 7.49 (m, 1H) 7.66 (t, J=6.10 Hz, 1H) 7.70 (s, 2H) 8.12 (d, J=7.32 Hz, 1H) 14.42 (m, 1H); MS (APCI−) m/z 550 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([C:19]1[C:20]([N:25]=[CH:26][N:27]([CH3:29])C)=[N:21][CH:22]=[CH:23][CH:24]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:7]2[CH:6]=[CH:5][C:4]([OH:16])=[CH:3][C:2]=2[NH:1][C:29]2[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=3[N:25]=[CH:26][N:27]=2)=[CH:10][CH:11]=1
Reactant: Nc1cc(O)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(O)cc2Nc2ncnc3ncccc23)cc1
Yield: 35.4 %

Procedure:
The product of Example 48B (380 mg, 1.63 mmol) was reacted with the product of Example 15A (284 mg, 1.63 mmol) using the procedure of Example 15E substituting the product of Example 48B for the product of Example 15D to provide a solid which was triturated with methanol to provide the title compound (209 mg, 35%).
Reaction SMILES: C(O)C.[H][H].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([O-])=O>[Pd].C1C=CC=CC=1>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: *O[SiH2]*
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1ccc(-c2ccc(N)cc2)cc1
Yield: 123.9 %

Procedure:
270 mg of 5%-Pd/C was suspended in 14 mL of a 1:1 mixed solvent of ethanol and benzene. While passing hydrogen through the system, a solution was added that consisted of 3.21 g of the 4,4'-dinitrobiphenyl-containing polysiloxane (average value of n: 14.4) synthesized in Reference Example 2 dissolved in 14 mL of the same mixed solvent. Hydrogen was injected into the system for 3 hours while stirring. The catalyst was then filtered off and the solvent was distilled under reduced pressure to give 3.00 g of the 4,4'-diaminobiphenyl-terminated polysiloxane as a viscous yellow liquid.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCOCC>CN(C=O)C.O>[CH2:32]([CH:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:3]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 71 %

Procedure:
To a suspension of NaH (160 mg, 4.0 mmol) in DMF (8 mL) at 0° C. under N2, was added benzyl tert-butyl malonate (1.0 g, 4.0 mmol) in DMF (2 mL). The mixture was stirred for 50 min after which 1-bromoundecane in DMF (2 mL) was added. After an additional hour of stirring the reaction was allowed to warm to room temperature. The reaction was maintained overnight. Et2O (100 mL) and water (20 mL) were added to partition the reaction. The aqueous phase was extracted with Et2O (100 mL), and the combined organics dried over Na2SO4. The solvent was evaporated and the residue purified by flash column (C18 12 g, 40-100% ACN/water+0.1% TFA) to yield the title compound as a colorless oil (1.14 g, 2.82 mmol, 71%): LCMS Method F Rt=1.58 min, M+Na 427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84-0.96 (m, 3H) 1.28 (br. s, 12H) 1.31 (m, J=3.90 Hz, 6H) 1.41 (s, 9H) 1.88 (q, J=7.38 Hz, 2H) 3.29 (t, J=7.58 Hz, 1H) 5.19 (q, J=12.27 Hz, 2H) 7.30-7.42 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[O:31])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:38][CH:39]=2)[C:21]2[CH:20]=[CH:19][C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(Nc1nn[nH]n1)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 μmol 3-cyanophenylisocyanate dissolved in 500 μL dichloroethane was added to the above resin bound 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (50 mg). Shaking the mixture for 5 hours at 25° C. followed by filtration and washing of the resin with 2×1 mL dichloromethane, 4×1 mL DMF, 2×1 mL H2O, 3×mL THF and 3×1 mL dichloromethane afforded the resin bound title compound.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:22]([O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[CH3:23].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:38])[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:2]3[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:17]=[C:16]5[C:12]([CH:13]=[CH:14][N:15]5[CH2:18][CH3:19])=[CH:11][CH:10]=4)=[CH:4][N:3]=3)[CH2:36][CH2:37]2)=[CH:30][CH:31]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc5ccn(CC)c5c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(1-Ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column chromatography with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C29H31N5O3 [M+H]+: 498.2500. Found: 498.2501.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH:19][CH:20]([C:25]([CH3:27])=[CH2:26])[C:21]([O:23]C)=O.C1CCN2C(=NCCC2)CC1.O>C1C=CC=CC=1>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:23])[C:20](=[C:25]([CH3:27])[CH3:26])[O:19][C:17]2=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OC
Reactant: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21
Solvent: c1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-fluoro-6-isocyanato-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.5 g) and methyl 2-hydroxy-3-methyl-3-butenoate (1.3 g) in benzene (50 ml), DBU (1.5 g) was added at room temperature. The resulting mixture was refluxed for 10 hours, cooled to room temperature, combined with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixture of toluene and ethyl acetate as the eluent to give Compound No. 9 (3.0 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([O-:10])=O)[C:4]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(O)(=O)C(O)=O.[CH2:25]([NH:27][NH2:28])[CH3:26]>>[CH2:3]([OH:7])[CH3:1].[CH2:25]([N:27]1[C:8](=[O:10])[C:5]2=[N:6][O:7][CH:3]=[C:4]2[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:28]1)[CH3:26]
Reactant: CCNN
Reactant: CCc1onc(C(=O)[O-])c1C(=O)c1ccccc1
Agent: O=C(O)C(=O)O
Product: CCO
Product: CCn1nc(-c2ccccc2)c2conc2c1=O
Temperature: 50 °C
Yield: 1021.5 %

Procedure:
A mixture of ethylbenzoylisoxazole-3-carboxylate (G. Renzi, V. Dal Piaz et al. Gazz. Chim. Ital., 1968, 98, 656) (0.25 g, 1.02 mmol) and polyphosphoric acid (2.5 g) was gently warmed at 50° C. until the solution became clear. Ethylhydrazine oxalate (0.5 g, 3.33 mmol) was added and the mixture was warmed at 90° C. for 5 hours. After cooling, ice-cold water was added and the precipitate was collected by filtration. The final product was purified by recrystallization from ethanol (0.24 g, 93% yield)
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24](=[O:41])[N:25]([C:32]2[O:40][C:36]3=[CH:37][CH:38]=[CH:39][C:35]3=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CCO.C1COCC1.O>[O:40]1[C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=[C:32]1[N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:16][CH:17]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[CH:5][CH:6]=1)=[O:41]
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a stirred solution of 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methylester (6) (0.42 g, 0.75 mmol) in EtOH/THF/H2O (4:2:1) (20 mL) at rt, was added aq. 40% NaOH (2.5 ml), The reaction mixture was stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure and the crude was acidified with 4N HCl (pH=2). The resulting mixture was extracted with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The resulting compound was dried under vacuum to afford 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid as a solid (0.35 g): 1H NMR (300 MHz, CD3OD): 10.23 (s, 1H), 7.78 (d, J=8.7 Hz, 4H), 7.55-7.66 (m, 4H), 7.20-7.40 (m, 9H), 6.10 (bt, 1H), 4.03 (t, J=7.2 Hz, 1H), 3.45 (dd, J=5.0, 9.0 Hz, 1H), 3.03 (dd, J=5.7, 12.9 Hz, 1H), 2.20-2.40 (m, 2H), 2.10-2.15 (m, 2H), 1.65-1.75 (m, 2H), 1.50-1.60 (m, 2H); LC-MS m/z=541 [C37H34NO3+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH:28]([CH2:29][C:30](O)=[O:31])[CH:24]([CH2:25][CH2:26][CH2:27]1)[CH2:23][CH2:22][CH2:21]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:24]12[CH:28]([CH2:29][C:30]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:31])[CH:20]([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:22][CH2:23]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CCCC1CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CCCC1CCC3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.12 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg and stirred at 0° C. for 30 min. 9-bicyclo[3.3.1]nonylacetic acid 97.0 mg and WSC 0.15 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 19 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(bicyclo[3.3.1]nonan-9-yl)acetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 41 mg and refluxed under heating for 1 hour. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[N:50]1([C:56](Cl)=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][N:32]([C:56]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:57])[CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCN(C(=O)N4CCOCC4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 82 %

Procedure:
(3R)-(2,6-Diphenyl-pyridin-4-yl)-[3-(piperazine-1-carbonyl)-[1,4′]bipiperidinyl-1′-yl]-methanone (0.507 mmol, 272 mg) was dissolved in anhydrous dichloromethane and N,N-diisopropylethylamine (2 eq. 180 μl) followed by N-morpholine carbonyl chloride (1 eq. 60 μl ) were added. After 3 hr a further aliquot of N-morpholine carbonyl chloride (40 μl) was added and the mixture was stirred at room temperature for 66 hr. The solution was washed with 0.1M sodium hydroxide solution, dried over anhydrous sodium sulfate, diluted with toluene and evaporated to dryness. The product was purified by chromatography on silica gel eluting with a 2.5% to 10% methanol-dichloromethane gradient to give the title compound (270 mg, 82%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:5]2)[CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Cl:32])[CH:23]=1)=[O:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH3:4].[Cl:32][C:24]1[CH:23]=[C:22]([NH:21][C:19]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5]3)[CH2:12][CH2:13]2)=[O:20])[CH:27]=[CH:26][C:25]=1[C:28]([F:31])([F:30])[F:29]
Reactant: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(Cl)(Cl)Cl
Reactant: C1C[C@@H](CN2CCNCC2)CN(C2CC2)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N
Product: O=C(Nc1ccc(C(F)(F)F)c(Cl)c1)N1CCN(C[C@@H]2CCCN(C3CC3)C2)CC1
Temperature: 150 °C
Yield: 82.4 %

Procedure:
A mixture of 1-{[(3S)-1-cyclopropylpiperidin-3-yl]methyl}piperazine (67 mg), 2,2,2-trichloro-N-[3-chloro-4-(trifluoromethyl)phenyl]acetamide (102 mg) and DBU (46 mg) in acetonitrile (4 mL) was heated to 150° C. in the microwave for 10 minutes. The solution was concentrated at reduced pressure and purified by reverse phase prep HPLC eluting with a mixture of 5-95% acetonitrile in water and then SCX-2 column eluting with methanol then 7M NH3 in methanol to give the title compound as a white solid (55 mg, 41%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][CH2:65][N:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:63][CH2:64][CH2:65][N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN2CCOCC2)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 4-(2-Aminoethyl)morpholine (82 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was recrystallised from DMSO to yield white solid (0.040 g, 62%).