Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:18]3[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Brc1cc2cccnc2c(Br)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nc(Br)cc3cccnc23)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
6,8-Dibromo-1,7-naphthyridine (3.464 g) was added to 1-ethylpiperazine (10 ml), and the resulting mixture was stirred at 100° C. for 15 min. The reaction mixture was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellowish orange solid (3.780 g, yield; 98%).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:15]2=[O:30])=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:30]=[C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:31])=[O:5])=[O:11])[CH:13]=2)[CH2:17][N:16]1[CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2

Procedure:
A solution of the ester (8) (252 mg, 0.60 mmol), TFA (4 ml) and CH2Cl2 (8 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated to dryness and the residue purified by flash chromatography (silica, EtOH/NH4OH 19:1) to provide (9) as off-white foam. NMR conforms to structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([CH3:42])[C:33]([CH:35]2[C:40](=O)[CH2:39][CH2:38][O:37][CH2:36]2)=O)[N:27]=1>CCO>[CH3:25][C:26]1[CH:30]=[C:29]([CH3:31])[N:28]([CH:32]([C:33]2[C:35]3[CH2:36][O:37][CH2:38][CH2:39][C:40]=3[N:17]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:18]=2)[CH3:42])[N:27]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(C)n(C(C)C(=O)C2COCCC2=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 3.9 %

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (86 mg, 0.28 mmol) and potassium carbonate (77 mg, 0.56 mmol) in EtOH (7 mL) were heated to 60° C. for 10 min followed by the addition of 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl)dihydro-2H-pyran-4(3H)-one (70 mg, 0.28 mmol). The reaction was stirred over night. Solvent was evaporated and the crude product was taken up in DCM and washed with water. The product was purified on a prepHPLC yielding 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (5.00 mg, 3.89%). MS (ES+) m/z 460.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(F)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-fluorophenol (6.00 g, 53.5 mmol), ethyl 4-bromobutanoate (15.70 g, 80.5 mmol) and Cs2CO3 (26.20 g, 80.4 mmol) in DMF (25 mL) under N2 was refluxed overnight. The mixture was then cooled to rt and 150 mL of water was added. The resulting mixture was extracted with DCM (100 mL×2) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (12.0 g, 99%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[NH2:5].CCCCC.O.[CH:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[N:5]=[CH:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CNC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)C=O
Solvent: CCCCC
Solvent: O
Product: CNC(=O)[C@H](CCSC)N=CC(C)(C)C

Procedure:
There were added to 40.0 grams (247 mmoles) of (S)-methionine mono-methylamide dissolved in 100 ml of n-pentane 27.5 ml (250 mmoles) of pivalaldehyde. The reaction mixture was boiled on the water separator until the formation of water ended (3 hours). The solvent was removed under reduced pressure and there remained behind 52.2 grams (92% of theory) of (S)-N-(2', 2'- dimethylpropylidene)-methionine mono-methylamide which was further processed without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl.CCN(CC)CC>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15](=[O:17])[CH3:16])[CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3,3-dimethyl-6-nitroindoline (450 mg) in CH2Cl2 (15 mL) and Et3N (0.6 mL) at −10° C. was added acetyl chloride (180 μL, 2.5 mmol). The mixture was stirred at rt overnight and quenched by addition of sat. aq. NaHCO3, and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column to give a light yellow solid (390 mg, 71% for two steps).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Pt](=O)=O>[CH3:1][CH:2]1[NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: CC1CCCC(C(=O)O)N1
Reaction time: 72 h
Yield: 95.4 %

Procedure:
6-Methyl-pyridine-2-carboxylic acid (4.11 g, 30 mmol) was mixed with platinum(IV) oxide (35 mg, 0.154 mmol) in ethanol (50 mL) and water (25 mL) and stirred under hydrogen for 3 days. The reaction mixture was filtered through the celite and concentrated to dry. The residue was triturated with diethyl ether to give 4.1 g (98.3%) of the title compound as a white solid. 1H NMR (CDCl3), δ(ppm): 3.39 (dd,1H), 3.11 (m, 1H), 2.28 (d, 1H), 1.88 (m, 2H), 1.35–1.67 (m, 3H), 1.32 (d, 3H).
Reaction SMILES: [O:1]=[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5]C)=O.[CH3:20][C:21]([Mg]Cl)([CH3:24])[CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1>[CH3:20][C:21]([CH3:24])([CH2:22][CH3:23])[C:3](=[O:5])[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:1]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)C1CCCNN1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Reaction time: 5 h
Yield: 69 %

Procedure:
A solution of methyl 2-oxo-2-[2-benzylperhydropyridazinyl]acetate (9.0 g, 29.4 mmol) in 30 ml dry THF was cooled to −78° C. and treated with 35 ml of 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at for 5 hours, the mixture was poured into saturated ammonium chloride (150 ml) and extracted into ethyl acetate. The organic layer was washed with water, dried and concentrated. The crude material was purified by silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 7.0 g product (69% yield) as clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.76 (t, 3H, J=7.0); 1.06 (s, 6H) 1.69 (m, 6H); 2.80 (m, 1H); 3.15 (m, 1H), 4.03 (m, 1H); 4.13 (m, 1H), 5.18 (m, 2H), 7.36 (m, 5H).
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([O:34][S:35](=[O:40])(=[O:39])[NH:36][CH2:37][CH3:38])[C:31]([CH3:41])=[CH:30][C:29]=1[S:42]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[C:29]([S:42][C:10]2[C:11](=[O:13])[O:12][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:8][C:9]=2[OH:14])=[CH:30][C:31]([CH3:41])=[C:32]([O:34][S:35](=[O:39])(=[O:40])[NH:36][CH2:37][CH3:38])[CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (156 mg, 0.499 mmol; prepared in Example NN), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 250 mg, 0.546 mmol), K2CO3 (303 mg, 2.195 mmol), and DMF (4 mL). The reaction was stirred at room temperature for 2.5 hours and then worked up in the usual manner. The crude product was flash chromatographed using CH2Cl2 :MeOH (98:2 to 97:3) to give the desired product as a amorphous solid. 1H NMR (CDCl3) δ 1.0-2.1 (m, 16 H), 1.55 (s, 9 H), 2.00 (s, 3 H), 2.6-2.7 (m, 3 H), 3.10 (d, 1 H), 3.3-3.4 (m,2 H), 4.96 (t, 1 H), 6.70-6.78 (d, s, 3 H), 6.93 (d, 2 H), 7.29 (s, 1 H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[CH2:48][NH2:49]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:49][CH2:48][C:44]3[S:43][CH:47]=[CH:46][CH:45]=3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NCc1cccs1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NCc4cccs4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and thiophen-2-ylmethanamine
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:60])([C:56]([F:59])([F:58])[F:57])[CH2:46][CH2:47][CH2:48][S:49][CH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:52]3[CH2:53][CH2:54][CH2:55][C@H:51]3[CH2:50][S:49][CH2:48][CH2:47][CH2:46][C:45]([F:44])([F:60])[C:56]([F:57])([F:58])[F:59])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC[C@@H]2Cc3cc(OCc4ccccc4)ccc3[C@H]3CC[C@]4(C)C(=O)CC[C@H]4[C@H]23)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Yield: 72.5 %

Procedure:
Under the conditions of Example 23h, 4.58 g of 3-benzyloxy-7α-(5-tosyloxypentyl)-estra-1,3,5(10)-trien-17-one is reacted with 3.17 g of (2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine, worked up, and the crude product is chromato-graphed on silica gel with hexane/ethyl acetate. 3.9 g of 3-benzyloxy-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentyl-thiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one is obtained as oil. [α]D22 =+32.5° (c=0.117 in chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][CH:30]=[C:31]([C:33]([O:35]C)=[O:34])[N:32]=2)[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][CH:30]=[C:31]([C:33]([OH:35])=[O:34])[N:32]=2)[CH2:24][CH:23]1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1csc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc(C(=O)O)cs2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 112 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylate were added 2.0 mL of THF, 1.0 mL of methanol and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at 60° C. overnight. To the mixture was added 1.1 mL of 1 M hydrochloric acid, followed by concentration under reduced pressure, and to the residue were added chloroform and anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 116 mg of a colorless foamy substance of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylic acid as a crude product.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[S:44][C:45]([CH:49]=O)=[C:46]([CH3:48])[N:47]=2)=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[S:44][C:45]([CH2:49][NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31][CH3:32])=[O:30])[CH2:21]3)=[C:46]([CH3:48])[N:47]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)c1cccc(N2CCCC(N)C2)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(N2CCCC(NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
Acetic acid (0.0251 mL, 0.438 mmol) and sodium triacetoxyborohydride (97.7 mg, 0.438 mmol) were added to methyl 3-(3-aminopiperidin-1-yl)benzoate (79.0 mg, 0.337 mmol) and 2-(4-chlorophenyl)-4-methylthiazole-5-carboaldehyde (80.1 mg, 0.337 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 16 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was added to make the mixture basic. The mixture was then extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=5:1->2:1) gave 59.4 mg (39%) of the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:16]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:46]([O:48][C:49](=[O:52])[CH2:50]Br)[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:52])[CH2:50][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:28][C:16]2=3)[CH2:27][CH2:26]1)[CH3:47]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Temperature: 50 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 120) (0.18 mmol) in DMF (3 mL), add bromo-acetic acid ethyl ester (0.54 mmol) and cesium carbonate (0.90 mmol). After heating the mixture at 50° C. for 30 minutes, cool to room temperature and dilute the reaction with water (15 mL) and extract with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-50%), to give the title compound as a colorless foam. MS (ES+): 736 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:21]([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[O:34])[CH2:22][CH2:23]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Cc1sc2nc(N)nc(N3CCNCC3)c2c1-c1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(C)c(-c5ccccc5)c34)CC2)cc1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of Example 11 (50 mg, 0.16 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 4-methoxyphenyl isocyanate (22 μL, 0.17 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1% to 2% methanol in dichloromethane), yielding the title compound (49 mg) as a white powder. 13C NMR δ (75 MHz, acetone-d6) 169.83, 161.99, 159.36, 155.05, 154.65, 135.58, 133.58, 130.55, 130.10 (2C), 127.84 (2C), 127.00, 126.13, 121.29 (2C), 113.26 (2C), 110.65, 64.94, 54.72 (2C), 49.33 (2C), 13.54. MS (m/z) 475 [M+H]+.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[C:1]12([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.7 mg (0.2 mmol) 1-adamantyl isocyanate, 20 mg (0.168 mmol) indoline and 51 mg (0.5 mmol) NEt3 in 2 mL DCM was shaken at room temperature overnight and evaporated to dryness. The residue was taken up in DMF and subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 15.2 mg (30%) of the title compound as white solid. MS(m/e): 297.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 32 g of 4-bromo-2-isopropylphenol, 25.7 g of benzyl bromide, 23 g of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction solution was poured into ice-water, acidified by adding 10% hydrochloric acid and then extracted with 500 ml of diethyl ether. Then, the ether layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30 g of 4-bromo-2-isopropylphenyl benzyl ether (yield, 65%).
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][OH:15]>>[C:1]1(=[N:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCCCCCCCCC1
Product: ON=C1CCCCCCCCCCC1

Procedure:
reacting cyclododecanone with hydroxylamine in an aqueous solution in the presence of an excess amount of cyclododecanone or a solvent to produce cyclododecanone oxime (hereinafter, referred to as an “oxime-forming step”);
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:5]([CH2:1][CH2:2][C:3]#[CH:4])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of 3-butyne-1-ol (21.0 g, 0.3 mol) in 100 mL of DMF was added imidazole (41.3 g, 0.6 mol), followed by a solution of t-butyldimethylsilyl chloride (48.0 g, 0.32 mol) in 25 mL of DMF. After stirring at room temperature under Ar for 18 h, the reaction mixture was poured into 10% aqueous NaHCO3 (150 mL) and extracted with hexane (3×250 mL). The organic phase was washed (brine), dried (Na2SO4) and evaporated to give 1-(t-butyl dimethylsiloxy)-3-butyne (49.0 g, 89%) as a colourless oil: IR (neat) 3320, 2125 (w) , 1260, 1110, 840 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ3.74 (t, J=7.2 Hz, 2H), 2.40 (dt, J=7.1, 2.6 Hz, 2H), 1.96 (t, J=2.6 Hz, 1H), 0.90 (s, 9 H), 0.07 (s, 6H).