Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:48])([CH3:47])[C:3]([O:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:26]=3)[CH:19]([CH3:21])[CH3:20])[CH:14]=2)[CH:9]=1)=[O:4]>C(O)(=O)C.[C].[Pd]>[CH3:48][C:2]([CH3:1])([CH3:47])[C:3]([O:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][NH:25][CH:26]=3)[CH:19]([CH3:21])[CH3:20])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: CC(C)C(O)(c1ccc2cc(OCOC(=O)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C(O)(c1ccc2cc(OCOC(=O)C(C)(C)C)ccc2c1)c1c[nH]cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yloxymethyl 2,2-dimethylpropionate (0.381 g) was dissolved in acetic acid (15 ml). To the solution was added palladium carbon (0.200 g), and the mixture was stirred at 50° C. for 2 h under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution. The organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=30:1→20:1) to give the titled compound (0.107 g) as an amorphous product.
Reaction SMILES: COP(=O)OC.[C:7](=O)([O-])[O-].[K+].[K+].[CH:13]1([N:16]2[C:20]([CH3:21])=[C:19]([CH:22]=O)[N:18]=[C:17]2[CH3:24])[CH2:15][CH2:14]1>CO>[CH:13]1([N:16]2[C:20]([CH3:21])=[C:19]([C:22]#[CH:7])[N:18]=[C:17]2[CH3:24])[CH2:15][CH2:14]1
Reactant: Cc1nc(C=O)c(C)n1C1CC1
Reactant: O=C([O-])[O-]
Agent: CO[PH](=O)OC
Agent: [K+]
Solvent: CO
Product: C#Cc1nc(C)n(C2CC2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.6 g, 3 mmol) was dissolved in 10 mL of methanol. Potassium carbonate (0.74 g, 5 mmol) was added. A solution of 1-Cyclopropyl-2,5-dimethyl-1H-imidazole-4-carbaldehyde (0.42 g, 3 mmol) in 5 ml methanol was added drop wise at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 15 mL water and extracted three times with ethyl acetate (15 ml each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 80:20→0:100 gradient) and the desired compound was obtained as a white solid (0.12 g, 30%), MS: m/e=161.4 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=1.274, method [7], MS(ESI) 433.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.35 (s, 1H), 8.23 (d, J=4.5 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2, 4.5 Hz, 1H), 7.12 (s, 1H), 4.91 (s, 2H) 3.34-3.33 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)C.[NH2:23][NH2:24]>CO>[NH:23]([C:4](=[O:3])[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[NH2:24]
Reactant: NN
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)OC(C)(C)C)cc2s1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc2nc(CC(=O)NN)sc2c1
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of Compound 188b (480 mg, 1.5 mmol) in methanol (15 mL) was added anhydrous hydrazine (0.19 mL, 6.0 mmol) and the mixture stirred for 16 h. The resulting precipitate was filtered, washed with three volumes of methanol and dried in vacuo to afford Compound 188c (400 mg, 87%) as white powder. LCMS=1.64 min using analytical method (B), 308.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J=1.1 Hz, 1H), 8.08 (dd, J=8.6, 1.8 Hz, 1H), 8.02-7.97 (m, 1H), 1.63 (s, 9H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C@H:12]([CH3:26])[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[OH:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:24])([OH:25])[CH3:23])[C@H:12]([CH3:26])[NH:11]1
Reactant: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
Dissolve tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (161 mg, 0.34 mmol) in ethyl acetate (962 μL). Cool on an ice bath. Add hydrogen chloride (843 μL, 3.37 mmol, 4M in dioxane) and stir on the ice bath for 4 hours. Concentrate under reduced pressure. Dissolve in ethanol and concentrate under reduced pressure to give the title compound (100 mg, 0.34 mmol). MS (m/z): 264.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([O:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:18])=[CH:15][C:14]=1[O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:32]=[CH:31][C:16]([C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:33][CH2:34][CH:35]1[CH2:36][CH2:37]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1OCC1CC1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reaction time: 2 h
Yield: 79 %

Procedure:
2-(benzyloxy)-2-oxoethyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate (2.6 g, 4.87 mmol) was suspended in EtOAc (30 ml) and MeOH (10 ml) in a 250 ml Parr bottle; 10% Pd/C (0.176 g, 0.165 mmol) was added; and the mixture was hydrogenated at the Parr apparatus for 2 hours (H2 pressure: 30 psi), then the catalyst was filtered over a pad of celite and the solvent was evaporated to dryness; 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-acetic acid was obtained as a white amorphous solid (1.7 g, 3.83 mmol, 79% yield, MS/ESI+ 465.9 [MNa]+) and used as such in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:28]#[N:29]>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C#N)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (310 mg, 731 μmol, see Example 53), dppf (162 mg, 292 μmol), tris(dibenzylideneacetone)dipalladium (66.9 mg, 73.1 μmol), copper cyanide (262 mg, 2923 μmol), and tetraethylammonium cyanide (126 mg, 804 μmol) were mixed in dioxane (6 mL) in a microwave tube under a nitrogen atmosphere. The reaction mixture was then stirred at 75° C. for 16 hours. The reaction mixture was returned to room temperature, fused to silica gel, and purified by silica flash chromatography (0-100% DCM/hexane) to give the desired ester as a white solid (163 mg). MS (m/e)=315.1 (M+H-tBu)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[C:12](=[NH:13])[O:18][NH:17][C:14]3=[NH:15])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: N#CC(C#N)C1CCC2(CC1)OCCO2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: N=C1NOC(=N)C1C1CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
A solution of 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-malononitrile (as prepared in the previous step, 0.207 g, 1.00 mmol) and hydroxylamine hydrochloride (Aldrich, 0.107 g, 1.54 mmol) in anhydrous pyridine (5 mL) were heated to 100° C. under a reflux condenser for 18 h. After cooling to ambient temperature and evaporation of the solvent in vacuo, the crude product was purified by thin layer chromatography on silica gel (10% methanol in dichloromethane) giving the title compound as an orange solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.037 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.142 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 159-161° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[NH:4]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C.O>[Si:14]([O:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[NH:4]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1N[C@@H](CO)CO1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1COC(=O)N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Under atmosphere of argon, a solution of (4S)-4-(hydroxymethyl)-1,3-oxazolidine-2-one (34.1 g) in N,N-dimethylformamide (300 mL) was added by imidazole (25.7 g) and was cooled down to the temperature of 0° C. To the mixture, a solution of tert-butyldimethylsilylchloride (48.2 g) in N,N-dimethylformamide (300 mL) was moderately dropped and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and water and was washed with saturated brine. The organic layer was dried over an anhydrous magnesium sulfate and concentrated to give the title compound (64.8 g) having the following physical data, which was used for the next reaction without purification.
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])([O-])=[O:17].[K+].[K+].O>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14]([NH2:15])=[O:17])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc(Br)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)C1(c2ccc(Br)cc2)CCC1
Temperature: 27 °C

Procedure:
H2O2 (30% 11.3 mL, 118 mmol) was added over 3 h to a stirred mixture of nitrile 1-2c (13.88 g, ˜58.9 mmol) and K2CO3 (1.62 g, 11.8 mol) in 59 mL of DMSO at 40-87° C., cooling with a water bath. The resulting mixture was cooled to 27° C. and water (100 mL) was added over 30 min. Crystalline product 1-3c formed. More water (100 mL) was added over 1 h. The resulting slurry was aged at RT for 16 h before filtration. The cake was rinsed with 100 mL of water and then with 100 mL of heptane. After drying in a vacuum oven at 50° C., product 1-3c was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[F:17]C1C=CC=C2C=1NC=C2C1CCNCC=1>>[F:17][C:3]1[CH:2]=[C:10]2[C:6]([C:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Fc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: Fc1cccc2c(C3=CCNCC3)c[nH]c12
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
Similarly prepared was 4-(7-fluoroindol-3-yl)-piperidine from 4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30]>O>[CH3:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][C:29]=1[NH:30][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 93.4 %

Procedure:
Isonicotinoyl chloride hydrochloride (466 mg, 2.61 mmol, commercially available product) and triethylamine (600 μl, 4.30 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of (S)-2-(2-methyl-1-piperidinyl)-5-(trifluoromethyl)aniline (223 mg, 0.863 mmol), obtained as described in [Referential Example 2-2]. The resulting mixture was warmed to room temperature and stirred for 19.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25 g, hexane/ethyl acetate=1.5/1). Thus, (S)—N-[2-(2-methyl-1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0613) (293 mg, 93.4%) was yielded as an colorless oily material.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CC1C=CC(S(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])(=O)=O)=CC=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOCCOCCNc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
K2CO3 (380 mg, 2.76 mmol, 2.5 equiv.) was added to a solution of 4-methoxyaniline (136 mg, 1.1 mmol, 1 equiv.) in 1 mL of DMF, and the resulting slurry was heated to 100° C. 2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8) (100 mg, 0.276 mmol, 0.25 equiv.), dissolved in DMF (1 mL), was then added to the reaction via syringe-pump over 5 hours. The reaction was stirred for an additional 12 hours, after which time it was concentrated under reduced pressure and partially purified (Silica Gel, 12 g RediSep pre-packed column, 0% EtOAc:Hexanes→20% EtOAc:Hexanes→50% EtOAc:Hexanes, followed by EtOAc flush). The material obtained after chromatography was carried directly on to the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(Cn2cc(N)cn2)o1
Product: CS(=O)(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-(5-methanesulfonyl-furan-2-ylmethyl)-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.94 min; [M+H]+=413.29.
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.C(OC([N:36]1[CH2:41][CH2:40][N:39]([C:42](=[O:45])[CH2:43]Cl)[CH2:38][CH2:37]1)=O)(C)(C)C>>[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[CH2:43][C:42](=[O:45])[N:39]2[CH2:40][CH2:41][NH:36][CH2:37][CH2:38]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCNCC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available 4-(2-Chloro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester as electrophile, the title compound was obtained as a white solid after removal of the Boc protecting group under standard conditions (TFA/dichloromethane, room temperature).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:18])[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13])=[O:9])=[O:4].COC(CC(C)C([N:27]1CCC[C@H]1C(O)=O)=O)=O>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:18])[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([NH2:27])=[O:13])=[O:9])=[O:4]
Reactant: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
By substituting the 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-proline of Example 24 for the 1-(3-methoxycarbonyl-2-methylpropanoyl)-L-proline in the procedure of Example 50, 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-prolineamide is obtained.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Reactant: Clc1ccccc1CBr
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1ccccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([S:8]([N:7]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(N(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To a solution of 4′-Methoxy-2′-nitro-p-toluenesulfonanilide (0.32 g (1.00 mmol)) in pyridine (1,0 ml), p-toluenesulfonyl chloride (0.20 g (1.05 mmol)) was added with stirring at room temperature. After 15 hours' stirring at room temperature, the reaction mixture was poured into water and crystals separated was filtered and washed to give 0.34 g (83%) of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[S:24]([O:1][CH2:2][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: OCC12CC(c3ccccc31)c1ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC23CC(c4ccccc42)c2ccccc23)cc1

Procedure:
9-Tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene by treatment with p-toluenesulfonyl chloride in the presence of a base in an inert solvent;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][N:24]([CH3:25])[CH3:23])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: CNC
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 4.78 g (14.2 millimoles) of the 7-chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine produced in step (a) in 150 ml of CH2Cl2 was saturated with dimethylamine gas at 0°. The flask was stoppered and the solution was stored at -15° for 16 hours.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH3:29][N:30]([CH2:32][CH2:33]Cl)[CH3:31]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Reactant: CN(C)CCCl
Product: Cc1cccc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 107 except that the compound of Example 120 was reacted with 2-(N,N-dimethylamino)ethyl chloride. mp 93° C., NMR, IR, MS 453.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]4[C:17]([C:18](=[O:21])[C:19]=3[OH:20])=[C:16]([O:22][CH3:23])[CH:15]=[CH:14][CH:13]=4)=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br>>[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:21])[C:19]=2[OH:20])=[C:16]([O:22][CH3:23])[CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: COc1cccc2oc(-c3ccc4c(c3)OCO4)c(O)c(=O)c12
Agent: BrB(Br)Br
Product: COc1cccc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c12
Yield: 40315552 %

Procedure:
The reaction was conducted according to the same procedure as Example 57 except that 60 mg (190 pmol) of the compound obtained in Example 4 instead of the compound obtained in Example 12 and 1.5 molar equivalents of boron tribromide (BBr3) were used. Then the resulting product was separated by preparative TLC to give 23 mg of the title compound in a yield of 40%.