Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(NC(C)C)(C)C.[I-]>CN(C)C=O.O>[CH:1]1([CH2:7][CH2:8][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCC1CCCCC1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [I-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCN(CCC2CCCCC2)CC1)c1ccccc1
Temperature: 70 °C

Procedure:
2-Cyclohexylethyl bromide (1.9 g.) in dimethylformamide (10 ml.) was added to 4-benzamidopiperidine (2.2 g.), diisopropylamine (4 ml.) and a trace ofsodium iodide in dimethylformamide (10 ml.). The mixture was heated at 70° C for 16 hours, cooled, poured into water, and extracted with methylene chloride. The washed and dried extracts were evaporated and the solid residue was recrystallised from ethanol to give the product (1.25 g.), m.p. 174°-5° C. (Found: C, 76.4; H, 9.5; N, 8.9. C20H30H2O requires C, 76.4; H, 9.6; N, 8.9%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:23]>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:23])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4-phenylbenzoic acid (5.46 g, 27.6 mmol) in methylene chloride (66 mL) was added 2 drops of DMF and oxalyl chloride (2.80 mL, 30.3 mmol). The reaction mixture was stirred overnight and added to a stirred solution of ice and ammonium hydroxide. The resulting precipitate was filtered, washed with methylene chloride, and triturated with water. The product was collected by filtration and dried in vacuo to yield 4-phenylbenzamide (3.88 g, 71%).
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH:15]([NH:17][OH:18])[CH3:16])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.[CH3:23][N:24]=[C:25]=[S:26]>>[CH3:21][C:19]([C:6]1[CH:7]=[C:8]([CH:15]([N:17]([OH:18])[C:25]([NH:24][CH3:23])=[S:26])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]=1[OH:4])([CH3:22])[CH3:20]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Reactant: CN=C=S
Product: CNC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 0.500 g (0.0016 mole) of 2,6-bis(1,1-dimethylethyl)-4-[1-(hydroxyamino)ethyl]phenol acetate is added 0.128 g (0.00175) of methyl isothiocyanate. The reaction mixture is stirred at room temperature for 18 hours and evaporated to near dryness. The residue is washed with Et2O and there is obtained 0.300 g (55%) white solid, m.p. 175°-175.5° C.
Reaction SMILES: [C-:1]1([C:6]2([CH2:11][CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][O:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]>FC(F)(F)C(O)=O>[C-:1]1([C:6]([C-:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)([CH2:11][CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][OH:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:20].[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:20]
Reactant: OCCCC1([c-]2cccc2)CCCO1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: O=C(O)C(F)(F)F
Product: OCCCC(CCCO)([c-]1cccc1)[c-]1cccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 207.3 %

Procedure:
One gram of 2-ferrocenyl-2-(3-hydroxypropyl)tetrahydrofuran (II) was dissloved in 10 ml of trifluoroacetic acid at 25°C for 2 hours. The trifluoroacetic acid was removed under reduced pressure at 25°C and ferrocene, 5.41 g (0.032 mole), dissolved in 25 ml of methylene chloride, was added to the residue. The solution was stirred 40 hours at 25°C and then treated with 50 ml of H2O and enough ascorbic acid solution (drop by drop) to reduce the ferricinium ion present. The phases were separated and the aqueous phase was extracted with 25 ml of methylene chloride. The methylene chloride phases were combined and dried over calcium chloride. The solvent (CH2Cl2) was removed under reduced pressure and the residue was heated at 175°/0.25 mm pressure of 15 minutes to remove residual unreacted ferrocene. The nonvolatile residue was then dissolved in a 2% methyl alcohol in ethyl acetate solution and chromatographed on a dry 3.6 cm by 25 cm alumina column. Extraction of the major yellow band with methyl alcohol gave 1.1 g (69% yield) of 4,4-diferrocenylheptane-1,7-diol (IV). Recrystallization from benzene gave a mp of 168°-171°C. An additional recrystallization from methyl alcohol gave a mp of 169°-171°C.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[N:10][CH:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1ccncc1)C(=O)c1ccc(C)c(C)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3ccncc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
273 g (0.88 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(pyridine-4-ylamino)-acrylic acid methyl ester 2f was dissolved in 30 mL of diphenyl ether and the resultant solution was heated at 250° C. After 2.5 h, the reaction solution was cooled to room temperature and diluted with 50 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was purified by washing with hexane to yield 119 mg of 3-(3,4-Dimethyl-benzoyl)-1H-[1,6]napthyridin-4-one 10a as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:28]([N:41]1[CH2:44][CH:43](O)[CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH:28]([N:41]1[CH2:44][CH:43]([O:12][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])[CH2:42]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2Cl)cc1

Procedure:
A solution of 2,4′-dichlorobenzhydrol (7) (178 mmol), p-toluenesulphonic acid (198 mmol) and 1-benzhydryl-3-azetidinol (1) (99 mmol) in toluene (500 mL) was heated at reflux in a Dean-Stark apparatus for 40 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; (10% ethyl acetate:isohexane)] to finish the product as a yellow oil (17.8 g, 38%).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=O)C(C)(C)C.C([O:45][CH2:46][C@@H:47]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[C:48]1[C:49]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]1[N:59]=[N:60][N:61]=[C:53]1[CH:52]=[CH:51]2)(=O)C(C)(C)C>>[C:70]([O:69][C@@H:47]([C:48]1[C:49]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]1[N:59]=[N:60][N:61]=[C:53]1[CH:52]=[CH:51]2)[CH2:46][OH:45])([CH3:73])([CH3:71])[CH3:72]
Reactant: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethanol (5 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H24ClN4O2: 411.2. Found: 411.1.
Reaction SMILES: [N-]=C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([C:36]2[S:40][CH:39]=[N:38][CH:37]=2)[CH:33]=[CH:32][C:31]=1[N:41]1[S:45](=[O:47])(=[O:46])[N:44](CC[Si](C)(C)C)[C:43](=[O:54])[CH2:42]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([C:36]2[S:40][CH:39]=[N:38][CH:37]=2)[CH:33]=[CH:32][C:31]=1[N:41]1[S:45](=[O:47])(=[O:46])[NH:44][C:43](=[O:54])[CH2:42]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CN(c2ccc(-c3cncs3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of PS-isocyanate resin (2.0 g) in THF (5 mL) is added tetrabutylammonium fluoride (1.0 M in THF, 2.17 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the filtrate is added to a solution of 5-(2-benzyloxy-4-thiazol-5-yl-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (272 mg, 0.543 mmol) in THF (1 mL) and the mixture is stirred at 50° C. for 18 h. The reaction mixture is cooled and diluted with EtOAc, washed with 1N HCl and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by column chromatography eluting with MeOH/EtOAc to afford the title compound as a yellow solid: (M+1)+=402.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH:13][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][NH:21]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Temperature: 85 °C
Reaction time: 21 h
Yield: 62.7 %

Procedure:
A mixture of (S)-1-(7-Bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine, (0.50 g, 1.84 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.61 g, 2.57 mmol) and DIPEA (0.60 mL, 3.31 mmol) in IPA (7 mL) was stirred at 85° C. in a sealed tube for 21 h. After cooling, the was mixture partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4), concentrated in vacuo and the residue purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (15 mL), treated with HCl/dioxane (4M, 2.0 mL, 8.0 mmol) then stirred for 10 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give 430 as a white solid (0.45 g, 63%). LCMS (Method K): RT 3.12 min [M+H]+ 390.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.99 (1H, s), 8.27-7.97 (3H, m), 7.62 (1H, dd, J=8.72, 4.66 Hz), 7.23-7.16 (1H, m), 5.76 (1H, m), 4.09 (3H, s), 1.67 (3H, d, J=6.76 Hz). Signals split due to presence of tautomers
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O.C1C=CC=CC=1>[CH2:22]([O:21][C:19]([C:18](=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]#[N:17])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC#N
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccc(C)cc1
Yield: 74.6 %

Procedure:
A mixture of 10 g (51 mmol) of 4-methylbenzophenone, 4.9 mL (46 mL (46 mmol) of ethyl cyanoacetate, 0.72 g (9.3 mmol) of ammonium acetate, 2.2 mL (37 mmol) of acetic acid and 8 mL of benzene was heated at reflux for 18 h using a Dean-Stark water separator. Then, 1.1 mL of acetic acid and 0.35 g of ammonium acetate was added and the mixture was heated for 24 h more. The solvent was removed and the residue was dissolved in chloroform and washed with water. The organic phase was dried over magnesium sulfate and the solvent was removed to yield a crude product. This was chromatographed on silica gel (hexane-ethyl acetate mixtures of increasing polarity) to afford 10 g of the title compound of the example as a colourless oil (yield: 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([C:15]1[CH:14]=[C:13]([CH3:12])[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
2.23 g (9.40 mmol) 3-bromo-4-fluoro-benzoic acid chloride, 1.40 g (9.40 mmol) 4-methyl-3H-benzoxazol-2-one and 5.01 g (37.60 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. After cooling to RT the mixture was mixed with ice water. The precipitate formed was suction filtered and washed with water. Then the precipitate was triturated with MeOH, suction filtered, washed with MeOH and dried i. vac.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10]C=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:6]([I:18])[C:5]2=[O:19].COC1C2[N:24]([C:38](=[O:49])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:40]=2)C=CC=1C(=O)C#CC1C=CC=CC=1>>[I:18][C:6]1[C:5](=[O:19])[C:4]2[CH:3]=[CH:2][N:24]3[C:38](=[O:49])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:40]=[C:10]3[C:9]=2[O:8][C:7]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(F)cc12
Reactant: COc1c(C(=O)C#Cc2ccccc2)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Product: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Yield: 81 %

Procedure:
Following the procedure used to prepare 6-fluoro-3-iodo-2-phenyl-chromen-4-one, 8-methoxy-7-(3-phenyl-propynoyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was reacted to give the title compound as a cream solid (958 mg, 81%). LCMS (Method A): RT=4.80 min, [M+H]+=536.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20]N3C4C=CC=CC=4N=N3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:30])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(NCn3nnc4ccccc43)cc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc(C2(CC(=O)OC(C)(C)C)CCCC2)cc1
Yield: 100.3 %

Procedure:
A stirred suspension of [1-(4-{(benzotriazol-1-ylmethyl)-amino}-phenyl)-cyclopentyl]-acetic acid tert-butyl ester (0.21 g) in ethanol (10 mL), under argon, was treated with sodium borohydride (0.051 g). After stirring at room temperature for 2 hours a further aliquot of sodium borohydride (0.017 g) was added and stirring was continued for a further hour, then a further aliquot of sodium borohydride (0.017 g) was added and stirring was continued for a further hour. The reaction mixture was then evaporated and the residue was treated with water (15 mL) and ethyl acetate (25 mL). The organic phase was separated and then washed with water (15 mL), then with brine (15 mL), then dried over magnesium sulfate and then evaporated to give the title compound (0.15 g) as an amber oil which crystallised on standing.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:13]1[CH2:14][CH2:15][C:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=3[NH:9][C:8]=2[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1c(C)cccc21
Product: CCOC(=O)C1=CN(C(C)=O)CCc2c1[nH]c1c(C)cccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A using ethyl 7-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and acetyl chloride; 1H-NMR (CDCl3): δ 10.50 (1H, br s), 8.12 (1H, br s), 7.36 (1H, d), 7.01 (2H, m), 4.39 (2H, q), 4.01 (2H, m), 3.16 (2H, m), 2.53 (3H, s), 2.39 (3H, s), 1.43 (3H, t); MS (ES): 313 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3C=C(C4C=CC(C5C=CN=CC=5)=CC=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[C:48]([CH3:50])[O:47][N:46]=2)=[CH:41][C:40]=1[O:51][CH3:52])#[CH:38]>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[N:49]=[C:48]([CH3:50])[O:47][N:46]=5)=[CH:41][C:40]=4[O:51][CH3:52])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(-c2noc(C)n2)cc1OC
Product: COc1cc(-c2noc(C)n2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-3-methoxy-phenyl)-5-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])N(OC)C)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:12](=[O:17])[CH3:19])[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of [1-(methoxy-methyl-carbamoyl)-cyclobutyl]-carbamic acid tert-butyl ester (11.5 g, 44.6 mmol) in THF (150 mL) at 0° C. was slowly added methylmagnesium bromide as a 3.0M solution in ether (37.2 mL, 111 mmol). The reaction was allowed to slowly warm to 25° C. and stirred for 24 h then quenched by the addition of saturated aqueous NH4Cl (100 mL). EtOAc (200 mL) was added and the layers were separated. The aqueous phase was extracted two more times with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), decanted and concentrated to afford a solid. The solid was purified via normal phase flash chromatography on silica gel (10-50% EtOAc-heptane) to afford (1-acetyl-cyclobutyl)-carbamic acid tert-butyl ester as a white solid (6.02 g, 63%).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][C@H:8]([NH:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:44])[CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH2:23]1)=[O:21])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:16][CH2:17][F:18])[CH:14]=1)(C)(C)C>C(O)=O>[F:18][CH2:17][CH2:16][O:15][C:13]1[CH:14]=[C:9]([C@@H:8]([NH:19][C:20]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:44])[CH2:29][CH2:30][CH:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)[CH2:23]2)=[O:21])[CH2:7][C:6]([OH:45])=[O:5])[CH:10]=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCF)c1
Solvent: O=CO
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cncc(OCCF)c1
Yield: 61.3 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-fluoroethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat (660 mg, 1.06 mmol) in formic acid (12 mL) was heated for 30 minutes to 60° C. and 10 minutes to 100° C. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to yield 311 mg of (3S)-3-[5-(2-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH3:8].N([O-])=[O:11].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1Br
Agent: [Na+]
Product: Cc1ccc(O)cc1Br

Procedure:
In a manner similar to that of Example 11(a), by reaction of 20 g (107 mmol) of 3-bromo-4-methylphenylamine with 8.9 g (129 mmol) of sodium nitrite, a brown oil is obtained, without purification (m=20 g; Y=100%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[I:12]N1C(=O)CCC1=O>C(O)(=O)C.O>[I:12][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[CH2:4]2
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)ccc2c1CC(=O)N2
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To 2 g of 4-methyl-2-oxindole in 40 mL of glacial acetic acid in an ice bath was added 3.67 g N-iodosuccinimide. The mixture was stirred for 1 hour, diluted with 100 mL 50% acetic acid in water and filtered. The resulting white solid was dried under high vacuum to give 3.27 g (88% yield) of the title compound as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:11][C:6]1([C:3]2([CH2:2][O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9][O:10]1
Reactant: CC1(C2(CO)CC2)OCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C

Procedure:
To a stirred and ice-cooled solution of 3 (5.0 g, 31.6 mmol), N,N-dimethyl-4-aminopyridine (386 mg, 8.16 mmol) and triethylamine (22 mL, 158 mmol) in dichloromethane (25 mL) was added p-toluenesulfonyl chloride (7.23 g, 37.9 mmol) portionwise and the mixture was stirred in a cold room at 4° C. overnight. The mixture was poured into ice water, and the organic layer was separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 16.70 g of crude 4, as a pale yellow oil, which was used in the next step without further purification.