Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH2:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1c(F)cc(Cl)c(N)c1Br
Product: CCOc1c(F)cc(Cl)c(NC(C)=O)c1Br
Yield: 76 %

Procedure:
A solution of 30-5 (16 g, 59.7 mmol) in acetic anhydride (50 mL) was stirred at room temperature for one hour. The precipitate was filtered and washed with ether to afford 30-6 (14 g, 76%) as a white solid. LRMS: calc 308.9 and found: 309.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH:27]12[CH2:35][CH:31]([CH2:32][NH:33][CH2:34]1)[CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:33]3[CH2:34][C@H:27]4[CH2:35][C@H:31]([CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]4)[CH2:32]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Product: C[C@@H](C(=O)N1C[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)C2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
Using (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid and 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester* and the synthetic procedure described in Example 1, the title compound was prepared. *Reference for 3,7-Diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester: Alstermark, C; Andersson, K; Bjore, A; Bjorsne, M; Lindstedt, A. E; Nilsson, G; Polla, M; Strandlund, G; Ortengren, Y. PCT Int. Appl. (2000), WO 0077000.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[C:4]([O:12][C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: OCCCc1ccc(Br)cc1OC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1ccc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
A solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.03 g, 3.44 mmol) in CH2Cl2 (47 mL) was cooled at 4° C. and added celite (1.4 g) and pyridinium chlorochromate (1.11 g, 5.16 mmol). The reaction mixture was stirred at ambient temperature for 6 hr and filtered through a pad of celite, concentrated, and purified by flash chromatography (silica gel, 16% EtOAc in hexane) to give 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde (659 mg, 64%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: COc1ccc(F)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(F)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 92.6 %

Procedure:
With 16.9 g of 2-bromo-4-fluoroanisol and 10.0 g of 5-chloroisatin as starting materials, 15.7 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [C:1]([C:5]1[S:19][C:8]2[O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[NH:12][C:13](=[O:14])[C:7]=2[CH:6]=1)(=O)[CH2:2][CH3:3].C([SiH](CC)CC)C>>[CH2:1]([C:5]1[S:19][C:8]2[O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[NH:12][C:13](=[O:14])[C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Agent: CC[SiH](CC)CC
Product: CCCc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
2-Propionylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g) was dissolved in trifuoroacetic acid (20 ml) and triethylsilane (2 g) was added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue were added chloroform and ethyl acetate and the precipitated crystals were collected by filtration. The obtained crystals were washed with diisopropyl ether to give 2-propylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (930 mg).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:35])[CH:8]([N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:35])[CH:8]([N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NOC(C)(C)C)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NO)cc1
Temperature: 0 °C

Procedure:
N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide (0.77 g, 1.55 mmol) is dissolved in methylene chloride (2.0 mL) and ethanol (0.1 mL) in a glass sealed tube, and the reaction is cooled to 0° C. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed at room temperature for 3 days. After that time, the solvent is removed, and the reaction is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (2% methanol/methylene chloride) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide, m.p. 72°-75° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].CCN(C(C)C)C(C)C>CN1CCCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: COc1ccccc1CN
Reactant: Nc1ncc(Br)nc1Br
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNc1nc(Br)cnc1N
Temperature: 90 °C

Procedure:
A solution of 1.00 eq. of (2) is dissolved in N-methylpyrrolidine (2 mL) at room temperature. To this solution is added 3.00 eq. of 2-methoxybenzyl amine and 0.4 mL Hunig's Base. The resulting solution is heated to 90° C. and stirred for 12–24 hours under nitrogen. The resulting mixture is partitioned between ethyl acetate and H2O. The aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified via flash chromatography to provide (4).
Reaction SMILES: COC1C=CC(C[N:10]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11]2)=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[C:28]1([CH:27]2[CH2:26][O:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][NH:10]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(c1ccccc1)CO2
Temperature: 70 °C
Yield: 92.1 %

Procedure:
To tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.11 mmol), Pd (500 mg, 4.70 mmol) and ammonium formate (697 mg, 11.05 mmol) was added methanol. The reaction mixture was then heated at 70° C. for 16 hours. The reaction mixture was filtered through a plug of celite and the solvent was concentrated in vacuo to obtain tert-butyl 9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (340 mg, 93%) as an oil. ESI-MS m/z calc. 332.4. Found 333.5 (M+1)+; Retention time: 1.21 minutes (3 min run).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[C:12]([C@H:18]2[O:23][CH2:22][C@@H:21]3[CH2:24][NH:25][CH2:26][CH2:27][N:20]3[CH2:19]2)=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.[N:38]1([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][C:50](O)=[O:51])=[N:47][CH:48]=2)[CH:42]=[N:41][N:40]=[N:39]1.C(Cl)CCl.[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:38]1([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][C:50]([N:25]3[CH2:26][CH2:27][N:20]4[C@H:21]([CH2:22][O:23][C@H:18]([C:12]5[C:13]([CH3:17])=[C:14]([C:9]([F:8])=[CH:10][CH:11]=5)[C:15]#[N:16])[CH2:19]4)[CH2:24]3)=[O:51])=[N:47][CH:48]=2)[CH:42]=[N:41][N:40]=[N:39]1
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1c([C@@H]2CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cn4)C[C@H]3CO2)ccc(F)c1C#N
Reaction time: 0.08 h

Procedure:
6-Fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile 2,2,2-trifluoroacetate (1404 mg, 3.610 mmol) was suspended in DCM (20 mL) then TEA (2.011 ml, 14.43 mmol) was added. The mixture was stirred for 5 min, and then HOBT (828 mg, 5.41 mmol), 2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acid (740 mg, 3.61 mmol), and EDC (1383 mg, 7.21 mmol) were added and the resulting mixture was stirred for 2 h. The reaction was poured into a brine/NaHCO3 mixture. The DCM layer was separated and dried over Na2SO4 then filtered and concentrated. The residue was purified by chromatography using 120 g ISCO Redisep column eluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system to yield 3-((3R,9aS)-8-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=463: 1H-NMR (600 MHz, CDCl3) δ ppm 9.10 (s, 0.5H), 9.084 (s, 0.5H), 8.919 (dd, J=14.4, 2.5 Hz, 1H), 8.053 (m, 1H), 7.681 (m, 1H), 7.609 (t, J=8.25 Hz, 1H), 7.048 (t, J=8.5 Hz, 1H), 4.785 (d, J=10.1 Hz, 1H), 4.587 (d, J=13.2 Hz, 0.5H), 4.484 (d, J=12.8 Hz, 0.5H), 3.947-4.095 (m, 4H), 3.497 (t, J=11 Hz, 0.5H), 3.477 (t, J=11.1 Hz, 0.5H), 3.384 (t, J=12.6 Hz, 0.5H), 2.94-2.875 (m, 1H), 2.83-2.777 (m, 2H), 2.548 (s, 3H), 2.409 (t, J=11.2 Hz, 0.5H), 2.251-2.16 (m, 2H), 2.129-2.084 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.C([Li])(C)(C)C.CN([CH:22]=[O:23])C>C1COCC1>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([CH:22]=[O:23])[CH:3]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858 moles) in 300 mL of dry THF cooled to −78° C. was added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at −78° C. and then quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was stirred for 20 min. and then poured into a separatory funnel and extracted with CH2Cl2. The organic extracts were washed with water, dried over Na2SO4, filtered and concentrated to give a brown oil. This oil was purified by LC 2000 chromatography, eluting with ethyl acetate/hexanes (5:95) to give 3-biphenylcarboxaldehyde.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[CH2:14]([N:16]([CH2:27][CH3:28])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:20](O)=O)[CH3:15]>>[CH2:27]([N:16]([CH2:14][CH3:15])[C:17]1[CH:18]=[C:19]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=3)[N:13]=2)[CH:23]=[C:24]([CH3:26])[N:25]=1)[CH3:28]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: N=C(NO)c1ccc(CCO)cc1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(CCO)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-4-(2-hydroxy-ethyl)-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=1.07*min; [M+1]+=353.11; 1H NMR (CDCl3): δ 1.25 (t, J=6.8 Hz, 6H), 2.50 (s, 3H), 2.98 (t, J=6.3 Hz, 2H), 3.63 (q, J=7.0 Hz, 4H), 3.95 (q, J=6.0 Hz, 2H), 7.02 (s, 1H), 7.10 (s, 1H), 7.41 (d, J=7.5 Hz, 2H), 8.15 (d, J=7.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: O=C(Cl)c1ccccc1F
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4ccccc4F)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 521.4 (M+H+).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:13]>C(O)C>[CH:1]1([NH:6][C:7](=[O:12])/[CH:8]=[C:9](\[NH2:13])/[CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CC(=O)CC(=O)NC1CCCC1
Solvent: CCO
Product: C/C(N)=C/C(=O)NC1CCCC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Acetoacetic cyclopentylamide (169.1 g, 1.00 mole) is dissolved in ethanol (100 ml) and thereto is passed ammonia gas, while the temperature is controlled below 30° C. by cooling with a water bath. After passing ammonia gas for about 3 hours, colorless crystals precipitate. The reaction mixture is allowed to stand at 0° C. overnight. The precipitates are separated by filtration and washed with diethyl ether to give the title compound (140.4 g, yield 85.6%) as colorless needles, m.p. 138°-139° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH:12]=[O:13])[CH:9]=[C:8]([C:14]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:24]=[CH:23]4)([OH:19])[C:15]([F:18])([F:17])[F:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:10]([CH2:11][CH2:12][OH:13])[CH:9]=[C:8]([C:14]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[N:24]=[CH:23]4)([OH:19])[C:15]([F:18])([F:17])[F:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a room temperature solution of (4-chloro-7-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[3,2-d]pyrimidin-5-yl)acetaldehyde (91 mg, 0.18 mmol) in 3 mL of THF was added NaBH4 (4 mg, 0.09 mmol, 0.5 equiv.). After 2 hours, the reaction was quenched with water and extracted with EtOAc. The organics were dried, filtered, and concentrated in vacuo. The residue was purified by HPLC (5-95% CH3CN/water 0.1% TFA). The desired peaks were combined, made basic with saturated aqueous sodium bicarbonate, and concentrated to remove excess CH3CN. The resulting aqueous layer was then extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 48 mg (53%) of the title compound as a white solid. MS m/z 506.34 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]2[NH:8][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)ncnc1C#Cc1ccccc1
Solvent: CN1CCCC1=O
Product: Clc1ncnc2cc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 251 (30.8 mg, 0.134 mmol) in NMP (1.4 mL) a suspension of KH in mineral oil (35%, 31 mL, 0.268 mmol) was added in one portion. The mixture was stirred at room temperature overnight and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography, eluent EtOAc/hexane (1:2) to afford title compound affording 252 (22.7 mg, 74% yield). MS (m/z): 230.1 (100%) 232.1 (33%) (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31]C)[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: COc1ccccc1-n1ncc2cc(C(O)(C(C)c3ccc(Cl)cc3Cl)C(F)(F)F)ccc21
Agent: BrB(Br)Br
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc2c(cnn2-c2ccccc2O)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-[1-(2-methoxy-phenyl)-1H-indazol-5-yl]-butan-2-ol (Example 189) was reacted with BBr3 to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=479.0 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[CH2:18]([CH:20]([C:21]1[C:22]([C:23]#[N:24])=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=2)[N:1]=1)[CH2:26][CH3:27])[CH3:19]
Reactant: CCC(CC)C(=O)CC#N
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Product: CCC(CC)c1nc2cc(OC)ccc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-4-methoxy-phenyl)-phenyl-methanone and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Colorless oil. MS (ESI): 331.4 (M+H)+.
Reaction SMILES: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1[NH:33][C@@H:34]1[C@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([OH:42])[C:36]([CH2:43][OH:44])=[CH:35]1.C(O)(C(F)(F)F)=O>>[CH:35]1[C@H:34]([NH2:33])[C@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([OH:42])[C:36]=1[CH2:43][OH:44]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 74.4 %

Procedure:
10 g of pure acarbose were place into 10% TFA solution at 5% final concentration. At a reaction temperature of 100° C., it was reacted for 12 hours or more, followed by removal of TFA and water. Then, by using ion-exchange resins for purification, 2.02 g of valienamine were obtained respectively.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(N2CCNCC2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of t-butyl 4-phenylpiperazine-1-carboxylate (500 mg, 1.91 mmol, 1.00 equiv) in DCM/CF3COOH (10/3 mL) was placed in a 50-mL round bottom flask and stirred for 1 h at 30° C. in an oil bath. The pH value of the solution was adjusted to 9 with aqueous sodium hydroxide (1 M), and the solution was extracted with 3×10 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate. Solids were removed via filtration, and the resulting solution concentrated under vacuum yielding 300 mg (97%) of 1-phenylpiperazine as yellow oil.
Reaction SMILES: [CH3:1][SiH:2]([CH3:10])[N:3]([CH2:7][CH:8]=[CH2:9])[SiH:4]([CH3:6])[CH3:5]>C1(C)C=CC=CC=1>[CH3:1][SiH:2]([CH3:10])[N:3]1[CH2:7][CH:8]([CH3:9])[Si:4]1([CH3:6])[CH3:5]
Reactant: C=CCN([SiH](C)C)[SiH](C)C
Solvent: Cc1ccccc1
Product: CC1CN([SiH](C)C)[Si]1(C)C

Procedure:
Into a 500-mL roundbottom flask were introduced 100 mL N,N-bis(dimethylsilyl)allylamine and 100 mL toluene and then 5 mg bis(triphenylphosphine)platinum dichloride (PtCl2 (PPh3)2).The reaction was heated for 1 hour at 80° C., and the reaction product was isolated and purified by distillation.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:3]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCNC1CCCC1
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a solution of 11.5 g (0.075 mole) of beta-alanine ethyl ester hydrochloride and 6.3 g (0.073 mole) of cyclopentanone in 200 mL of dichloromethane was added 6.5 g (0.082 mole) of sodium acetate and 22.5 g (0.107 mole) of sodium triacetoxyborohydride. The mixture was stirred 24 hours and then quenched by the addition of 200 mL of saturated sodium bicarbonate solution. After 20 minutes, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 12.0 g of 3-cyclopentylamino-propanoic acid ethyl ester, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[C:26]([CH3:31])[N:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[CH:27]=[C:26]([CH3:31])[N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Reactant: Cc1cc(I)cc(F)n1
Product: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)cc(F)n1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 98, step 4) and 2-fluoro-4-iodo-6-picoline (CAS RN: [884494-45-5]) was prepared the title compound as colorless oil, MS (ESI+): m/z=412.1 ([M+H]+, 1Br).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1cccc(Oc2ccnc(NC(C)=O)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1cc(Oc2cccc(CCC(=O)O)c2)ccn1
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of methyl 3-(3-{[2-(acetylamino)pyridin-4-yl]oxy}phenyl)propanoate (184 mg, 0.59 mmol) in MeOH (5 mL) was added 1N NaOH solution (702 μL, 0.70 mmol). The reaction was stirred for 18 h. The solvents were evaporated and the residue was dissolved in water and acidified to pH=1 by addition of 1N HCl solution. The precipitate was filtered off and washed with water then hexane and dried under vacuum to yield the title compound as a white solid (112 mg, 63.7%). LCMS: (FA) ES+ 301.2 (M+1), ES− 299.3 (M−1).