Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([Br:52])=[CH:51][C:46]=4[NH:45][C:44]3=[O:53])[CH2:39][CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[C:47]4[CH:48]=[CH:49][C:50]([Br:52])=[CH:51][C:46]=4[N:45]([S:59]([CH3:58])(=[O:61])=[O:60])[C:44]3=[O:53])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4cc(Br)ccc43)CC2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-5-bromo-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 12 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29]>>[OH:30][C:28]([C:27]([F:32])([F:31])[F:26])=[O:29].[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccccc3)n2)CC1
Product: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccnc(N3CCNCC3)n2)cc1

Procedure:
This compound was synthesized from tert-butyl 4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate as described for example 46 step 4 (400 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. MS (ESI) m/z: Calculated for C14H16N4: 240.14. found: 241.0 (M+H)+
Reaction SMILES: CS[C:3](=[N:18][CH2:19][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[NH:11][CH:12]2[CH2:15][S:14][CH2:13]2)=[C:6]([CH3:17])[CH:5]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[CH:26]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[CH2:19][N:18]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([NH:11][CH:12]4[CH2:15][S:14][CH2:13]4)=[O:16])=[C:6]([CH3:17])[CH:5]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[CH:26]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(C(=O)NC2CSC2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example I19) (16 mg) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (see WO 2007/125984) (12 mg) in THF (2 ml) was added at −5° C. tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (1.5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:2) to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (20 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.30 (s, 1H), 5.45 (m, 1H), 4.90 (d, 1H), 4.45 (d, 1H), 3.82 (d, 1H), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].[C:11]([N:14]1[CH2:18][C:17](=O)[N:16]=[CH:15]1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1nn(C)c(N)c1C
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1c(C)c(C)nn1C

Procedure:
5-Amino-1,3,4-trimethyl pyrazole hydrochloride (8.00 g.) and 1-acetyl-2-imidazolinone (7.05 g.) were reacted as described in Example I to give 7.90 g. mp 212°-215° (crystallized from CH3CN)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:9][CH:8]=1
Reactant: NCC(N)=O
Reactant: Fc1ccc(N=C=S)cc1
Product: NC(=O)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Glycinamide (5.0 g) and 4-fluorophenyl-isothiocyanate (9.18 g) were stirred in (200 mL). The mixture was heated at reflux for 5 minutes then stirred at ambient temperature for 20 minutes. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(4-fluorophenyl)-thioureido]-acetamide (10.7 g) as a light pink solid, m.p. 168°-170° C. (dec.). Mass spectrum (EI, M.+) m/z 277. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.97 (broad s, 1 H), 7.82 (broad s, 1 H), 7.45-7.52 (m, 3 H), 7.10-7.17 (m, 3 H), and 4.06 ppm (s, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCNC(=O)C3)c2s1
Temperature: 180 °C

Procedure:
The title compound was prepared by a method similar to that described in Example 2. 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (100 mg, 291 μmol), piperazin-2-one (44 mg, 436 μmol) and N,N-diisopropylethylamine (152 μl, 873 μmol) were combined in NMP (2 ml) and heated to 180° C. for 18 hrs. The mixture was cooled to RT, diluted with H2O and filtered. The solids were washed with H2O and air-dried. Both the solid and solution were collected, dissolved in DMSO and purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient). The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:11]C(=O)C.C(O)C.Cl>O>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: CC(=O)Nc1ccc2[nH]cnc2c1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]cnc2c1Cl
Temperature: 85 °C

Procedure:
58 mg (0.277 mmol) of N-(4-chloro-1H-benzimidazol-5-yl)acetamide (24-1) was suspended in a mixture of water, ethanol and concentrated HCl (0.06:1:0.4) for a total of 1 mL. The suspension was stirred and heated at 85° C. under nitrogen for 1 hour and after this time everything was soluble. The heat was turned off the solution was stirred overnight. The reaction was quenched with saturated NaHCO3. The pH was adjusted to 8 by adding solid NaHCO3 and Na2CO3. Extracted the reaction with ethyl acetate, dried, filtered and evaporated to recover the desired product 24-2. MS (M+1): measured 168.2; theoretical 167.0. 1H NMR (CD3OD): 6.75 (dd, 1H), 7.37 (d, 1H), 7.93 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3].CS([C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=1)(=O)=O.S([O-])([O-])(=O)=O>CN(C=O)C>[CH2:1]([C:5]1[O:6][C:7]([C:10]2[C:15]([O:16][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ncc(-c2c(O)cccc2Cl)o1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2-c2cnc(CC(C)C)o2)n1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
2 ml DMF solution containing 0.5 g 2-isobutyl-5-(2-chloro-6-hydroxyphenyl)oxazole, 0.41 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.55 g pottasium sulfate was stirred for 14 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and was then extracted with ethyl acetate. The organic layer obtained was washed with water and was then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduce pressure. The residue obtained was purified by using silica gel column chromatography, where hexane-ethyl acetate solution in a mixing ratio of 6:1 is used, affording the objective substance in an amount of 0.64 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 5-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-pentanoic acid, ethyl ester (0.409 g, 0.573 mmol) and 1N KOH (1.15 ml) in THF (6 ml) and methanol (3 ml) was stirred under nitrogen. After ˜18 h, the reaction mixture was concentrated. in vac. The residue was suspended in water (25 ml) and acidified with 2 N HCl (1.15 ml) then extracted with EtOAc (3×25 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the title compound as a light yellow foam (0.249 g, 63%); dec.>50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.67-1.76 (m, 2H), 1.87 (t, J=7.0 Hz, 2H), 3.16-3.27 (m, 4H), 4.12 (t, J=7.0 Hz, 2H), 6.37-6.38 (m, 1H), 6.94-6.99 (m, 1H), 7.06-7.10 (m, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.40-7.52 (m, 6H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 cm−; mass spectrum [(+)APCI], m/z 685 (M+H)+; Anal. Calcd. for C40H42Cl2N2O4: C, 70.07; H, 6.17; N, 4.09, Found: C, 69.66; H, 6.17; N, 3.85.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH2:13])([O-:3])=[O:2].N1C=CC=CC=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:26]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2n[nH]c3ccc([N+](=O)[O-])cc23)c1
Temperature: 25 °C

Procedure:
To a solution of 5-nitro-1H-indazol-3-ylamine in pyridine (Ryan Scientific, 0.150 g, 0.838 mmol) cooled to about 0° C. in an ice bath, was added 3-dimethylamino-benzoyl chloride (0.154 g, 0.838 mmol). The reaction mixture was stirred as it warmed to ambient temperature. After about 1 hour it was poured into crushed ice, then extracted with EtOAc (10 mL). The organic solvent portion was washed with a 1M aqueous HCl solution, then concentrated and dried under reduced pressure. The residue was further purified via preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile/0.1 M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to obtain 3-dimethylamino-N-(5-nitro-1H-indazol-3-yl)-benzamide as a white solid (0.002 g, 0.006 mmol); RP-HPLC (Table 1, Method e) Rt 1.95 min; m/z: (M+H)+ 326.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:4]=1[CH:5]=O.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:4]=1[CH:5]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc2c(cc1C=O)OCO2
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Yield: 90.6 %

Procedure:
A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde (16.0 g, 0.089 mol), diethyl malonate (15.0 ml, 0.090 mol), piperidine (4.4 ml, 0.044 mol) and acetic acid (2.5 ml, 0.045 mol) in benzene (75 ml) was stirred at reflux, equipped with a Dean-Stark apparatus, for 24 h. Upon removal of the solvent the crude residue was extracted with ethyl acetate and washed with 10% sodium carbonate solution, water, dried (Na2SO4). After removing the solvent, flash chromatography of the residue (silica gel, 25% ethyl acetate/hexane) provided the title compound as a yellow solid (26.0 g, 91%).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3]([N:5]1[N:9]=[C:8]([NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][C:6]1([CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][OH:35])=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].N1C=CC=CC=1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].Cl>O.ClCCl>[O:35]([CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:6]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([C:3](=[O:4])[C:2]([CH3:36])([CH3:1])[CH3:37])[N:9]=[C:8]([NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7]1)[Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO)(c2ccccc2)S1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C(=O)NC1=NN(C(=O)C(C)(C)C)C(CCCC(=O)NCCO[Si](C)(C)C(C)(C)C)(c2ccccc2)S1)c1ccccc1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To 4-[3-(2,2-dimethylpropionyl)-2-phenyl-5-(2-phenylpropionylamino)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-N-(2-hydroxyethyl)butanamide (1.21 g, 2.31 mmol) obtained in Step 4 mentioned above was added dichloromethane (20 mL), and the mixture was stirred at 0° C. Then, to the mixture were added pyridine (0.470 mL, 5.77 mmol) and tert-butyldimethylsilyl chloride (869 mg, 5.77 mmol), and the mixture was stirred at room temperature for 3 hours. To the mixture were added 1 mol/L hydrochloric acid (20 mL) and water (30 mL), and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue was added diisopropyl ether, and the deposited white solid was collected by filtration. The resulting solid was washed with water and diisopropyl ether, and dried under reduced pressure to give N-[2-(tert-butyldimethylsiloxy)ethyl]-4-[3-(2,2-dimethylpropionyl)-2-phenyl-5-(2-phenylpropionylamino)-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanamide (1.25 g, 85%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>C(O)C>[C:18]([N:22]1[C:8]([NH2:9])=[CH:7][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.5 %

Procedure:
A solution of pivaloylacetonitrile (300 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 days, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, ethyl acetate to 20% methanol in ethyl acetate) to afford the product as an off-white solid (123 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](Cl)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25]C)[CH2:19][CH2:20][NH2:21].[CH2:27](N(CC)CC)C.O>CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[OH:25])[CH:12]([C:8]1([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11]1)[N:21]([CH3:27])[CH2:20][CH2:19]2
Reactant: COc1ccc(CCN)cc1Cl
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CN1CCc2cc(Cl)c(O)cc2C1C1(c2ccc(Cl)cc2)CCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (20 g) in ether (50 ml) was added to a stirred mixture of 3-chloro-4-methoxyphenethylamine (16.2 g), triethylamine (13 ml) and ether (100 ml). After one hour, water (50 ml) was added and the mixture extracted with ethyl acetate. The organic layer gave a residue which was recrystallised twice from industrial methylated spirits. A portion of the product (12.6 g) was warmed with polyphosphate ester (70 ml). The resulting solution was heated at 90° C. for 48 hours, cooled and added to a mixture of ice, concentrated ammonia solution and ether. The ether layer was washed, dried and added to sodium borohydride (5 g) in ethanol (200 ml) and the mixture heated under reflux for 90 minutes. The ether evaporated during this time and then the ethanol was removed. Water (200 ml) was added and the resulting mixture extracted with ether. The extract was added to a mixture of 1M aqueous sodium phosphite solution [prepared from phosphorous acid (16.4 g), sodium bicarbonate (16.8 g) and water 200 ml)], 37-40% aqueous formaldehyde solution (130 ml) and methanol (300 ml). The ether was removed by evaporation and methanol (250 ml) added. The mixture was then heated under reflux for 16 hours and then the methanol was removed by evaporation. The residue was basified with aqueous ammonia solution and extracted with ether. The solvent was removed from the extract and the residue dried by azeotropic distillation with industrial methylated spirits and then with propan-2-ol. The dried residue was crystallised from propan-2-ol to give a solid which was further purified by high performance liquid chromatography. A sample of this purified product (1 g) was heated at 110°-115° C. under nitrogen with glacial acetic acid (10 ml) and 48% hydrobromic acid (10 ml) for 6 hours. The reaction mixture was then cooled and partitioned between ether and 50% aqueous potassium carbonate solution. The ether layer yielded 6-chloro-1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (m.p. 168°-171° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12](C2C=CC(C)=CC=2)[CH:11]=1.[CH:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32](Cl)Cl)=[CH:27][CH:26]=1.O.Cl[CH2:37][CH2:38]Cl>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:32]([NH:31][C:28]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)[N:16]([C:13]3[CH:14]=[CH:15][C:37]([CH3:38])=[CH:11][CH:12]=3)[C:12]=2[CH:11]=1
Reactant: ClCCCl
Reactant: COC(=O)CCCCCOc1ccc(N)c(-c2ccc(C)cc2)c1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(Nc3ccccc3)n(-c3ccc(C)cc3)c2c1

Procedure:
250 mg of 6-[3-(4-methylphenyl)-4-aminophenyl]oxyhexanoic acid methyl ester was dissolved in 1 ml of 1,2-dichloroethane, the solution was mixed with 0.1 ml of phenylisocyanide dichloride, and the mixture was heated for 8 hours to 65° C. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from a mixture that consists of ethyl acetate and diethyl ether. 147 mg was obtained.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:10].[CH3:11][O:12][CH2:13][CH2:14][Br:15]>>[BrH:15].[CH3:11][O:12][CH2:13][CH2:14][N:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[S:3][C:2]1=[NH:10]
Reactant: Nc1nc2c(s1)COCC2
Reactant: COCCBr
Product: Br
Product: COCCn1c2c(sc1=N)COCC2

Procedure:
A mixture of product of Example 218A (1.0 g, 6.4 mmol) and 2-bromoethyl methyl ether (3.0 mL, 32.0 mmol) was processed according to the method of Example 2A to afford the title compound: MS (LC/MS) m/z 213 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:34]([N:36]2[CH:40]=[N:39]C=C2)=[O:35])C=1.[C:41]([C:45]1[CH:46]=C(N)N[N:49]=1)([CH3:44])([CH3:43])[CH3:42].N1(C2C=CN=CC=2)CCCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:34](=[O:35])[NH:36][C:40]3[NH:39][N:49]=[C:45]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:46]=3)[CH:24]=[CH:23]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CN(C)C=O
Product: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
A solution of 4-(1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (210 mg, 0.55 mmol), CDI (179 mg, 1.10 mmol), TEA (230 uL, 1.65 mmol), and DMF (5 mL) is stirred at rt 1 h before 5-tert-butyl-2H-pyrazol-3-ylamine (77 mg, 0.55 mmol) and 4-pyrrolidinopyridine (16.4 mg, 0.11 mmol) are added. After 24 h, the reaction is concentrated in vacuo and the purified via FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 546.3 (M+1).
Reaction SMILES: O=[C:2]([CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>[Pt]>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:2]([CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)CCCCCCCC(=O)O
Reactant: NCc1ccc(F)cc1
Agent: [Pt]
Product: CC(C)C(CCCCCCCC(=O)O)NCc1ccc(F)cc1

Procedure:
Using the procedure of example I step D and starting from 9-oxo 10-methyl undecanoic acid and para fluorobenzylamine then hydrogenating in the presence of a platinum catalyst dl 9-(para fluorobenzylamino) 10-methyl undecanoic acid is obtained melting at 78°-82° after recrystallisation from acetonitrile.