Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C)=[O:9])[C:5](=[O:12])[NH:4][NH:3]1.[OH-].[Na+].Cl>>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5](=[O:12])[NH:4][NH:3]1
Reactant: COC(=O)Cn1c(=O)[nH][nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(=O)[nH][nH]c1=O
Yield: 32.5 %

Procedure:
0.5 g (2.9 mmol) of methyl 3,5-dioxo-1,2,4-triazolidine-4-acetate was stirred at room temperature for 2 hours with 8.7 ml (8.7 mmol) of 1-M sodium hydroxide solution. The resulting solution was acidified with concentrated hydrochloric acid and evaporated to dryness. The solid residue was extracted with hot acetonitrile. The acetonitrile extracts were evaporated and the residual colourless solid was recrystallized from acetonitrile, there being obtained 0.15 g (33%) of 3,5-dioxo-1,2,4-triazolidine-4-acetic acid of melting point 220°-223° C. (from acetonitrile).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([O-:4])=[O:3].C([O-])(O)=O.[Na+].[S:18](N)([NH2:21])(=[O:20])=[O:19].Cl>O>[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:9][S:18]([NH2:21])(=[O:20])=[O:19])([O-:4])=[O:3]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: NS(N)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1

Procedure:
A solution of 3-nitrobenzylamine hydrochloride, (1.89 g, 10.0 mmol) in water (10 mL) is treated with NaHCO3 (840 mg, 10.0 mmol) and sulfamide, (960 mg, 10.0 mmol). The mixture is heated at reflux for 5 h. The cooled mixture is acidified to pH 2 with 1N aqueous HCl and the precipitate is filtered, washed with water and dried under vacuum at 50° C. to afford 3-nitrobenzyl sulfamide as a tan solid: [M−1]−=230.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][CH3:83])/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)[C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[S:64])=[C:57](C(=O)C)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1CCOCC1.[F:90][C:91]([F:104])([F:103])[S:92]([O:95][CH2:96][CH:97]1[CH2:102][CH2:101][O:100][CH2:99][CH2:98]1)(=[O:94])=[O:93]>C(N(CC)CC)C.N1C=CC=CC=1>[F:103][C:91]([F:90])([F:104])[S:92]([O:95][CH2:96][CH:97]1[CH2:98][CH2:99][O:100][CH2:101][CH2:102]1)(=[O:93])=[O:94].[C:24]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:81]/[O:82][CH3:83])/[C:50]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[S:64])=[C:57]([CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:58][S:59][C@H:54]23)=[O:51])[N:48]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: OCC1CCOCC1
Agent: O=S(=O)(OCC1CCOCC1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCOCC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
Tetrahydropyran-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27(a) from tetrahydropyran-4-yl-methanol (348 mg), pyridine (0.27 ml) and trifluoromethanesulfonic acid anhydride (931 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (866 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27(b), followed by reacting the resulting reaction product with the tetrahydropyran-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27(b). The reaction solution so obtained was post-treated in the same manner as in Example 27(b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (904 mg; 98%).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22]([N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH:39]=[CH:40][C:41]([O:43][CH3:44])=[O:42])=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O1CCCC1>[CH2:1]([N:8]([C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C@@H:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:30][CH2:31][CH2:32]2)[CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C[C@H](c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
A solution of (S)-N-benzyl-α-methylbenzylamine (2.6 ml) in anhydrous tetrahydrofuran (50 ml), cooled to −70° C. and under nitrogen, was treated dropwise with a solution of butyllithium in hexanes (5 ml, 2.5M) over about 5 minutes to give a red solution. After stirring at −70° C. for a further 40 minutes the mixture was treated dropwise with a solution of methyl 3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)acrylate [2.0 g, Reference Example 7(d)] in tetrahydrofuran (20 ml) over about 10 minutes. Stirring was continued at low temperature for a further 20 minutes and then the reaction mixture was allowed to warm to room temperature. The mixture was partitioned between ether and water, the layers separated, and the organic layer washed with water then with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (initially 1:9 and then 15:85, v/v) to give the title compound as a viscous, colourless oil, 1.5 g.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1.[O:17]=[C:18]([NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[NH4+].[OH-]>CCOC(C)=O.CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:36]3[CH2:37][CH2:38][C@@H:34]([NH:33][C:18](=[O:17])[CH2:19][NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=4)[CH2:35]3)[CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCC=CC2=O)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2=O)cc1
Yield: 53.1 %

Procedure:
A slurry of water (19 μL, 0.10 mmol), 1-(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (42 mg, 0.207 mmol) and N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (130 mg, 0.41 mmol) was heated to 90° C. overnight. The crude mixture was subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to yield the title compound as a white solid (57 mg, 53%). 1H-NMR (CD3OD) δ: 1.70-1.82 (m, 1H), 1.83-2.00 (m, 1H), 2.15-2.37 (m, 2H); 2.40-2.58 (m, 1H), 2.56-2.81 (m, 4H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H), 3.79 (s, 3H), 4.04 (s, 2H), 4.38-4.47 (m, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.69 (t, J=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.22 (s, 1H). MS m/z: 519 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].Cl>N1C=CC=CC=1>[CH2:30]([O:32][N:33]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])=[CH:17][C:16]=2[Cl:28])=[N:8][CH:9]=1)[CH3:2])[CH3:31]
Reactant: CCON
Reactant: CC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a mixture of 0.41 g of 5-acetyl-2-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)pyridine and 10 ml of pyridine was added 0.17 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 89%) of 5-(1-(N-ethoxyimino)ethyl)-2-(3-(2,6-dichloro-4-(3, 3-dichloro-2-propenyloxy)-phenoxy)propyloxy)pyridine, nD24.5 1.5701.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)=S>[Hg]=O.O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(NC(=S)NC2CCN(C)CC2)c1
Agent: O=[Hg]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(NC3CCN(C)CC3)nc2c1
Yield: 100 %

Procedure:
A mixture of 44 parts of N-(2-amino-5-methoxyphenyl)-N'-(1-methyl-4-piperidinyl)thiourea, 38.9 parts of mercury(II) oxide and 270 parts of tetrahydrofuran was stirred and refluxed for 2 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel first using a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia, (85:15 by volume) as eluents. The pure fractions were collected and the eluent was evaporated, yielding 50.5 parts (100%) of 5-methoxy-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine as a residue (interm. 27).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=2)[N:7]=[C:6]1CC#N)[CH3:4].[C:21]([OH:24])(=[O:23])[CH3:22]>O.CS(C)=O>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=2)[N:7]=[C:6]1[CH2:22][C:21]([OH:24])=[O:23])[CH3:4]
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1CC#N
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
930 mg sodium hydroxide in 6 mL water was added to 525 mg (1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl)-acetonitrile in 2 mL DMSO. The reaction was stirred 4 h at 100° C. The mixture was diluted with water acidified with concentrated acetic acid and extracted with ethylacetate. The organic layer was dried and evaporated. The residue was crystallized with diethyl ether to give 60 mg of the desired product. Rt: 0.94 min (method K), (M+H)+: 263
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH2:18][C:19]([OH:21])=O)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:23]([OH:25])[CH3:24]>[Zn]>[C:23]([N:8]1[C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:19](=[O:21])[CH2:18][CH2:17][CH:6]([C:5]=23)[CH:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:25])[CH3:24]
Reactant: CCO
Reactant: O=C(O)CCc1c(-c2ccccc2)[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [Zn]
Product: CC(=O)N1c2cc(Cl)cc3c2C(CCC3=O)C1c1ccccc1
Yield: 20 %

Procedure:
6-chloro-2-phenylindole-3-propionic acid (19.5 g) synthesized as in Example 1, step 1 was suspended in ethanol (200 ml), and to the suspension were added zinc powder (42.5 g), then conc. hydrochloric acid (50 ml). The mixture was heated to reflux for 3 hours. In the meantime, two portions (50 ml and 20 ml) of conc. hydrochloric acid were further added 1 hour and 2 hours later respectively. After allowing the mixture to cool, the zinc was filtered off and the filtrate was diluted with water, adjusted to about pH 4 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to yield 4.2 g (20%) of the titled compound as a pale yellow syrup.
Reaction SMILES: O[CH2:2]CCC1CCN(CC2C=CC=CC=2)C(N)C1.[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:33]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]>>[C:19]([C:22]1[CH:23]=[C:24]([N:28]([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:2]2)[C:29]([NH:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:36][CH2:37]2)=[O:30])[CH:25]=[CH:26][CH:27]=1)(=[NH:21])[NH2:20]
Reactant: NC1CC(CCCO)CCN1Cc1ccccc1
Reactant: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCC2)c1
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCC2)c1

Procedure:
This material was prepared from 4-(3-hydroxypropyl)-amino-1-benzylpiperidine by the same route employed in the synthesis of N-(3-amidinophenyl)-N′-(1-benzylpiperidin-4-yl)cyclopentylurea. There was obtained 26 mg of the desired product as the bis-tifluoroacetic acid salt after purification by reverse phase HPLC. LRMS (M+2H)2+ m/z 196.7, (M+H)+ m/z 392;1H NMR (CD3OD): d 2.23 (m, 6H), 3.21 (bt, 2H), 3.58 (t, 2H, J=5.12 Hz), 3.62 (m, 2H), 4.39 (m, 3H), 4.53 (t, 2H, J=5.12 Hz), 7.51 (m, 5H), 7.62-7.78 (m, 3H), 7.81 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4([C:31]([CH3:34])([CH3:33])[CH3:32])[O:30][CH2:29][CH2:28][O:27]4)=[C:20]([CH3:35])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:36]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:31]([C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:36][C:9]=4[CH:10]=3)([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:19][C:20]=2[CH3:35])[O:30][CH2:29][CH2:28][O:27]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 2-{1-[4-(2-tert-butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid methyl ester (1.51 g, 3.05 mmol) in methanol (5.0 mL) and THF (5.0 mL) and is treated with NaOH (2.0 M, 10 mL). The resulting mixture is stirred at RT for 2 h. The mixture is concentrated and neutralized with HCl (1 N) till pH˜3, and extracted with EtOAc (3×50 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (1.43 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.I[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:21])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: CI
Reactant: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1Cl

Procedure:
In analogy to Example 1, steps 4 and 5, 5-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one was alkylated with iodomethane to give 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one which was further converted to the title compound. Colorless foam. MS (m/e, ISP neg. ion)=421.8 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=2[F:28])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[C:19]([F:28])=[C:20]([F:27])[C:21]([F:26])=[C:22]([F:25])[C:23]=2[F:24])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1
Product: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1)c1cc(Cl)ccc1O
Yield: 23.8 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,3,4,5,6-pentafluorophenyl)-thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[B:38](OC)([O:41]C)[O:39]C.B(F)(F)F.CCOCC>CCCCC.C1COCC1>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[C:14]1[B:38]([OH:41])[OH:39])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Reactant: COB(OC)OC
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of tert-butyllithium (1.7 M, 4.55 mL, 7.73 mmol, 2.00 equiv) in pentane was added to a solution of tert-butyl 5-{[4-(tert-butoxycarbonyl) piperazin-1-yl]sulfonyl}-1H-indole-1-carboxylate (2-2, 1.80 g, 3.87 mmol, 1 equiv) in THF (100 mL) at −78° C. The resulting orange-colored reaction mixture was stirred at −78° C. for 1.5 hour before trimethyl borate (1.10 mL, 9.66 mmol, 2.50 equiv) was added. The mixture was warmed to 0° C. and stirred for 20 minutes. Boron trifluoride diethyl etherate (1.20 mL, 9.66 mmol, 2.50 equiv) was then added, and the resulting mixture was partitioned between aqueous half-saturated ammonium chloride solution (200 mL) and EtOAc (2×200 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-(tert-butoxycarbonyl)-5-{[4-(tert-butoxycarbonyl) piperazin-1-yl]sulfonyl}-1H-indol-2-ylboronic acid (2-3) as a tan solid. LCMS [M+H]+ observed=510.3; calculated=510.4.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>O>[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Trans-4-aminocyclohexane carboxylic acid hydrochloride (2.00 g, 14.3 mmol) was added in small portions to a stirred, hot (70-85° C.) solution of Red-Al (27.0 g) for 2 h (a semisolid formed), and heating was continued overnight. After 24 h, the reaction mixture was cooled to room temperature and treated with a solution of NaOH (3.8 g) in H2O (34 ml). Following the addition, the reaction was gradually heated to 80° C., and cooled. The toluene layer was separated and the aqueous layer was extracted with CHCl3 (3×100 ml). The organic layers were dried with MgSO4 and then concentrated under reduced pressure to provide the desired compound (1.81 g, 14.0 mmol) as a pure white solid in 50% yield. ES-MS: 130 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(N)cn1
Yield: 139.6 %

Procedure:
A solution of dimethyl-(5-nitro-pyridin-2-yl)-amine (100 mg, 0.47 mmol) and 10% palladium on carbon (0.05 g) in methanol (5 mL) was shaken under 50 psi hydrogen atmospheres at room temperature for 3 h. The reaction mixture was then filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layers were collected, concentrated, and dried to give N2,N2-dimethyl-pyridine-2,5-diamine (90 mg crude) as a light red oil, which was directly used in the next step without further purification.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:27])[N:15]([CH2:28][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C:14](=[O:38])[N:13]([CH3:39])[C:12]=2[N:11]=1.[Cl-].[NH4+]>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:18]2[C:17]3[C:16](=[O:27])[N:15]([CH2:28][CH2:29][CH2:30][O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[C:14](=[O:38])[N:13]([CH3:39])[C:12]=3[N:11]=[C:10]2[O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:25][CH:24]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of cyclopentanol (67 mg, 0.78 mmol) in THF (5 mL) was added sodium hydride (39 mg, 0.98 mmol) at 0° C. After stirring at 0° C. for 30 min, 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.2 g, 0.39 mmol, intermediate 14) was added. The mixture was stirred at room temperature for 16 h; then aqueous ammonium chloride solution (2 mL) was added at 0° C. The reaction mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude solid product. This material was slurried in ice cold ethanol, collected by filtration, and dried under vacuum to give 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (180 mg, 89.5% yield) as white solid. LCMS retention time 2.085 min; LCMS MH+-THP 433.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([O:28][C:29]2[C:34]([CH2:35][N:36]([CH3:47])[CH:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)=[C:33]([CH3:48])[N:32]=[C:31]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[CH:56]([OH:59])[CH2:57][CH3:58])[CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:23]1([O:28][C:29]2[C:34]([CH2:35][N:36]([CH3:47])[CH:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)=[C:33]([CH3:48])[N:32]=[C:31]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[C:56](=[O:59])[CH2:57][CH3:58])[CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(O)c1c(F)cccc1-c1cc(OC2CCCC2)c(CN(C)C2CCCc3ccccc32)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1c(F)cccc1-c1cc(OC2CCCC2)c(CN(C)C2CCCc3ccccc32)c(C)n1
Reaction time: 2 h

Procedure:
Dess-Martin reagent (170 mg, 0.4 mmol) is added to a solution of 1-[2-(4-cylopentyloxy-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridin-2-yl)-6-fluoro-pheny]-propan-1-ol (160 mg, 0.32 mmol) in DCM (4 mL) at room temperature and the resulting mixture is stirred for 2 hours. Saturated Na2S2O3 is added to the mixture and stirred for 10 minutes. The organic layer is separated and extracted with DCM (2×10 mL). The combined organic layers are dried and solvent is removed in vacuo to give 1-[2-(4-cylopentyloxy-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridin-2-yl)-6-fluoro-pheny]-propan-1-one which is used in the next step without further purification.