Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:28](OS(C(F)(F)F)(=O)=O)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([O:18][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 97.8 %

Procedure:
A solution of alcohol 32 (550 mg, 1.98 mmol) and 2,6-lutidine (0.34 mL, 2.97 mmol) in CH2Cl2 (20 mL) was cooled to −78° C., and 0.55 mL (2.39 mmol) of TBSOTf was added. The cold solution was stirred and allowed to warm to 0° C. over a 1 h. MeOH (40 μL, 1 mmol) was then added and the resulting mixture was concentrated via rotary evaporation. The crude residue was purified with flash column chromatography (EtOAc/hexanes; 1:5) to afford 760 mg (98%) of 33 as colorless oil. [α]20D=+126.7 (c=0.80, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.86-7.90 (m, 2H), 7.50-7.64 (m, 3H), 7.09 (d, J=5.4 Hz, 1H), 6.06 (dt, J=11.7 Hz, 1.5 Hz, 1H), 5.80 (dd, J=11.7 Hz, 5.1 Hz, 1H), 3.66 (dd, J=6.3 Hz, 2.1 Hz, 1H), 2.70 (m, 1H), 2.47 (m. 1H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H), 0.81 (s, 9H), 0.038 (s, 3H), 0.032 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 142.8, 140.4, 140.2, 137.8, 133.2, 129.3, 128.0, 118.4, 76.8, 41.4, 38.8, 26.0, 19.1, 18.2, 16.7, −4.1, −4.4; LRMS (CI): m/z 393 [M+H]+; HRMS (CI) calculated for C21H32O3SSi, 392.1841; found, 392.1840.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28](O)=[O:29])=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:35][CH:33]([CH3:34])[CH2:32][NH:31][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:23])([F:25])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:29]
Reactant: CC(O)CN
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C(=O)NCC(C)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 66.1 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-hydroxy-propyl)-amide (56 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 1-amino-2-propanol (14 mg), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 496.6. 1H NMR (DMSO-d6, 400 MHz): δ 12.27 (s, 1H), 8.32 (t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26 (s, 1H), 4.85 (d, 1H), 4.00 (s, 3H), 3.85-3.76 (m, 1H), 3.64 (s, 3H), 3.43-3.34 (m, 1H), 3.24-3.14 (m, 1H), 1.10 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:6]1[CH2:5][C:4](=[O:7])[N:3]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1([CH3:12])[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Product: CC(=O)N1CC(=O)N(CC(N)=O)C1(C)C

Procedure:
A solution of 2,2 dimethyl-5-oxo-1-imidazolidineacetamide (1.7 g) in acetic anhydride (9 ml) was stirred at 70°-80° C. for 5 minutes. The precipitate was collected and washed with acetone, affording the title compound as a white powder, m.p. 188°-189° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6].C(N(CC)CC)C.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.Cl>CN(C=O)C.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:34]3[CH2:39][CH2:38][S:37][CH2:36][CH2:35]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(CCl)cc2)nc1)c1ccc(Cl)c(Cl)c1
Reactant: C1CSCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccc(CN3CCSCC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3,4-dichloro-N-[6-(4-chloromethylphenoxy)-pyridin-3-yl]benzamide (0.61 g, 1.5 mmol) was dissolved in DMF (5 mL). To the resulting solution were added triethylamine (0.84 mL, 6.0 mmol) and thiomorpholine (0.15 mL, 1.5 mmol), and this solution was stirred overnight at 40° C. The resulting reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=80:1). The obtained solid (0.56 g, 1.18 mmol) was dissolved in ethyl acetate (50 mL), and a solution of 4 N hydrogen chloride in ethyl acetate (0.295 mL, 1.18 mmol) was added, and this solution was stirred for 1 hour at room temperature. The precipitated crystals were collected by suction filtration, and recrystallized from methanol, to thereby yield 0.38 g of the title compound.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:34][CH2:35]1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-1-methylpiperidine (236 mg, 0.93 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give a viscous brown solid (236 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.70 (d, J=7.5 Hz, 2H), 7.25 (d, J=7.5 Jz, 2H), 3.26-3.23 (m, 2H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 5H), 1.92-1.91 (m, 4H), 1.33 (s, 12H); MS ESI 302.2 [M+Na]+, calcd for [C18H28BNO2+Na]+ 302.22.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and acetic anhydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4C=CC([N+]([O-])=O)=C[CH:26]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:44]([C:46]1[N:50]=C(CO)[O:48][N:47]=1)[CH3:45]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:26]4[O:48][N:47]=[C:46]([CH2:44][CH3:45])[N:50]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCc1noc(CO)n1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1noc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)n1
Yield: 60.9 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.23 g (0.5 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 1 (step 1.5.), 0.128 g (0.99 mmol) of N,N-diisopropylethylamine, 0.030 g (0.25 mmol) of N,N-dimethylaminopyridine and 0.067 g (0.50 mmol) of 3-ethyl[1,2,4]oxadiazol-5-ylmethanol, and after chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.138 g of pure product is obtained in the form of a white powder.
Reaction SMILES: C[Si](N=C=O)(C)C.[CH2:8]1[CH:16]2[N:11]([CH2:12][CH2:13][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=4)[NH:19][CH:18]=3)[CH2:15]2)[CH2:10][CH2:9]1.[CH3:27][N:28](C)[CH:29]=[O:30]>>[CH3:27][NH:28][C:29]([NH:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:14]1[CH2:15][CH:16]2[N:11]([CH2:10][CH2:9][CH2:8]2)[CH2:12][CH2:13]1)=[O:30]
Reactant: Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N=C=O
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trimethylsilyl isocyanate (288 mg, 2.50 mmol) was added to a solution of 3-(octahydroindolizin-7-yl)-5-amino-1H-indole (322 mg, 1.26 mmol) in 5 ml of dimethylformamide. The reaction was stirred at room temperature for 24 hours. TLC indicated consumption of starting material so the reaction was concentrated to give a purple foam which solidified. This material was chromatographed on a FLUORISIL™ column using 20% methanol in methylene chloride (ammonium hydroxide) as solvent to give 164 mg of product. (43.7%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])=[CH:5][CH:4]=1)[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1
Reactant: NCc1nc(C(F)(F)F)no1
Product: CCc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-ethylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BS) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 473.1054 (M−H)−.
Reaction SMILES: [C:1]([C:4]([NH:9][CH2:10][C:11]1[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].O>CO.C(OCC)(=O)C.O1CCCC1>[C:1]([C:4]([NH:9][CH2:10][C:11]1[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:12]=1[C:13]([OH:15])=[O:14])([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1cc(CC)cnc1CNC(C)(C(N)=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1cnc(CNC(C)(C(N)=O)C(C)C)c(C(=O)O)c1
Yield: 60.7 %

Procedure:
A solution of 5.6 g of ethyl 2-{[(1-carbamoyl-1,2-dimethylpropyl)amino]methyl}-5-ethylnicotinate (0.0174 mol) in 30 mL of methanol containing 2 g of NaOH (0.05 mol) and 10 mL water is stirred at room temperature for two hours and 30 minutes. The reaction is concentrated in vacuo and redissolved in 30 mL water; adjustment of the pH to 4 with concentrated hydrochloric acid and concentration in vacuo gives a gum. This residue is dissolved in a mixture of ethyl acetate, tetrahydrofuran, and methanol, dried over MgSO4, and concentrated in vacuo to 6 g foam. Crystallization from methanol-ether affords 3.1 g product, mp 180°-181° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:33])[CH2:9][CH2:10][C@H:11]2[C@H:16]3[C@H:17]4[C@H:26]([CH2:27][CH2:28][C@:14]3([CH3:15])[C:13](=[O:32])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([C:29](O)=[O:30])=[CH:23][CH:24]=2)[CH2:19][CH2:18]4)=[N:4][CH:3]=1.N.C[N:36]1CCOCC1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:33])[CH2:9][CH2:10][C@H:11]2[C@H:16]3[C@H:17]4[C@H:26]([CH2:27][CH2:28][C@:14]3([CH3:15])[C:13](=[O:32])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([C:29]([NH2:36])=[O:30])=[CH:23][CH:24]=2)[CH2:19][CH2:18]4)=[N:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: Cc1cnc(NC(=O)CC[C@@H]2CC(=O)[C@@]3(C)CC[C@@H]4c5ccc(C(=O)O)cc5CC[C@H]4[C@H]23)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Cc1cnc(NC(=O)CC[C@@H]2CC(=O)[C@@]3(C)CC[C@@H]4c5ccc(C(N)=O)cc5CC[C@H]4[C@H]23)s1

Procedure:
0.5 g 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxylic acid is dissolved in DCM. 3 eq NH3 solution (0.5 M in 1,4 dioxane), 3 eq 4-methyl morpholine, 1.75 eq hydroxybenztriazole and 2 eq EDCl are added slowly in an ice-bath and the reaction is carried out as described in Example 1. Purification by column chromatography (EtOAc/EtOH, 6:1) gives pure 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxamide (EXAMPLE 3)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCNCc2ccccc2)CC1
Reaction time: 48 h
Yield: 43 %

Procedure:
Benzylamine (345 μl, 3.22 mmol, 1.1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (0.9 g, 2.93 mmol, 1 eq) and triethylamine (0.8 ml, 5.86 mmol, 2 eq) in toluene (50 ml), and refluxing was carried out for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in ethyl acetate (100 ml), washed with water (30 ml) and sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, ethyl acetate), a yellow solid was obtained. Yield: 43% (400 mg, 1.25 mmol).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[O:30][CH:31]=[C:32]([CH3:34])[N:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]1[O:30][C:29]([CH3:28])=[N:33][C:32]=1[CH3:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1c(-c2ccccc2I)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: Cc1coc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)o1
Temperature: 140 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a vial are added 5-[1-tert-butyl-2-(2-iodo-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (50 mg, 0.107 mmol), 2,4-dimethyl-oxazole (21 mg, 0.216 mol), palladium(II) acetate (5 mg, 0.022 mmol), PPh3 (6 mg, 0.023 mmol) and Cs2CO3 (70 mg, 0.215 mmol) in DMF (1.5 mL). The reaction mixture is stirred at 140° C. for 18 hours. The reaction mixture is diluted with EtOAc/water. The organic layer is separated, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-5% MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (19 mg, 41%) as an off-white solid. LCMS (ESMS): m/z 439.86 (M++1)
Reaction SMILES: [P:1](Cl)(=[O:18])([O:10]CC1C=CC=CC=1)[O:2]CC1C=CC=CC=1.C([O:27][C:28]1[CH:33]=[C:32]([O:34]COCC)[C:31]([CH:39]([CH3:41])[CH3:40])=[CH:30][C:29]=1[C:42]1[N:46]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH3:56])[CH:51]=[CH:50]3)[C:45](=[O:57])[N:44](C(OCC2C=CC=CC=2)=O)[N:43]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[P:1]([OH:18])([OH:10])([O:34][C:32]1[CH:33]=[C:28]([OH:27])[C:29]([C:42]2[N:46]([C:47]3[CH:48]=[C:49]4[C:53](=[CH:54][CH:55]=3)[N:52]([CH3:56])[CH:51]=[CH:50]4)[C:45](=[O:57])[NH:44][N:43]=2)=[CH:30][C:31]=1[CH:39]([CH3:41])[CH3:40])=[O:2]
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: CCOCOc1cc(OCc2ccccc2)c(-c2nn(C(=O)OCc3ccccc3)c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc3c(ccn3C)c2)c(O)cc1OP(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dibenzyl phosphorochloridate was added to the solution of benzyl 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylate and potassium carbonate in acetone. The reaction mixture was stirred at room temperature overnight. After removal of solvent, the reaction mixture was purified by column chromatography to produce pale yellow oil, which was hydrogenated to give the desired.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][CH:53]=[CH:52][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[C:37]3[N:38](COCC[Si](C)(C)C)[C:39](=[O:43])[CH2:40][CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[CH:13][CH:12]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.COC(C)(C)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:55]=[CH:54][CH:53]=[CH:52][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[C:37]3[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH2:42][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)CCC3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2NC(=O)CCC3)cc1

Procedure:
A solution of 0.345 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-oxo-1-(2-trimethylsilanylethoxymethyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-ylmethoxy)piperidine-1-carboxylate in 4 ml of tetrahydrofuran is admixed with 0.85 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction solution is heated to reflux over 4 hours. A further 0.85 ml of tetrabutylammonium fluoride solution is added and the reaction solution is subsequently heated to reflux over a further 20 hours. The reaction solution is cooled and admixed with 50 ml each of water and tert-butyl methyl ether. The aqueous phase is removed and extracted with 40 ml of tert-butyl methyl ether. The combined organic phases are washed with 40 ml of brine, dried over sodium sulphate, filtered and concentrated to dryness. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (3:1 EtOAc-heptane); Rt=4.34.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
N-tert-Butoxycarbonylpiperazine (2.94 g, 16.0 mmol) was dissolved in pyridine (8 mL) under nitrogen and the solution cooled to 0° C. Methanesulfonyl chloride (1.5 mL, 19.3 mmol) was added. After 5 minutes, more pyridine was added (5 mL) and the reaction mixture was allowed to warm to ambient temperature. After 40 minutes, the pyridine was removed in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with 0.1M citric acid (3×125 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum to give 3.84 g (92%) of N-tert-butoxycarbonyl-N′-methylsulfonylpiperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:22][CH2:21]2)=O)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.P(Cl)(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH2:15][CH2:16][N:17]=[C:18]2[C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:22][CH2:21]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCNC(=O)C2(c3ccccc3OC)CC2)ccc1OCc1ccccc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3OC)CC1)=NCC2
Reaction time: 0.17 h

Procedure:
A mixture of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropane carboxamide (30.3 g) in acetonitrile (450 ml) and phosphoryl chloride (50 ml) was heated under reflux for 80 minutes. The solvent was evaporated in vacuo below 50° C. and the residue washed with ethyl acetate and then stirred with ethyl acetate (300 ml) and ice-cold 5% aqueous ammonia solution (200 ml) for 10 minutes. The organic layer was dried over potassium carbonate and the solvent removed by evaporation to give 7-benzyloxy-6-methoxy-1-[1-(2-methoxyphenyl)cyclopropyl]-3,4-dihydroisoquinoline.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:5]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:11][C:10]([CH2:12][CH3:13])=[C:9]([CH:8]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:7])[CH2:20][CH2:21]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(CC)c(C(=O)OC)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(CC)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a round-bottom flask, were added a solution of 2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500 mg, 2.12 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 470 mg, 2.12 mmol, 1 equiv), EDC.HCl (810 mg, 4.24 mmol, 2.00 equiv), and 4-dimethylaminopyridine (520 mg, 4.24 mmol, 2 equiv) in N,N-dimethylformamide (15 mL). The reaction was stirred overnight at 25° C. Upon reaction completion, the reaction mixture was diluted with 30 mL of ethyl acetate, then washed with 1×20 mL of NH4Cl (aq.) and 1×20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with a solvent mixture of ethyl acetate and petroleum ether (1:1) to yield 500 mg (60%) of the title compound as a pale yellow solid.