Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: C=CCN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A solution of 3.3. g of allyl isocyanate in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 6.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride, with stirring. When the exothermic reaction has subsided, stirring of the reaction mixture is continued at 20° to 25° C. for a further hour and the solvent is then evaporated off. The residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 13.2 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-allylurea are obtained. Melting point: 187°-188° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:7]([OH:9])=O)[C:2]#[CH:3].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:45](=[O:46])[N:32]2[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[NH2:40])[CH2:35][S:36][C@H:31]12>O1CCCC1.C(=O)(O)[O-].[Na+].O.CC(C)=O.CN(C)C=O>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:7]([NH:29][CH:30]1[C:45](=[O:46])[N:32]2[C:33]([C:42]([OH:44])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[NH2:40])[CH2:35][S:36][C@H:31]12)=[O:9])[C:2]#[CH:3]
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
2-(2-Propynyl)oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.2 g) was suspended in tetrahydrofuran (15 ml). Phosphorus oxychloride (1.0 g) was added thereto at 0° to 5° C. and the mixture was stirred for 20 minutes at the same temperature. Trimethylsilylacetamide (0.5 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (1.0 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0° to 5° C., dimethylformamide (0.5 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was added dropwise at -5° to 5° C. and pH 6.5 to 8.5 to a solution, which was prepared by adding acetone (10 ml) and tetrahydrofuran (10 ml) to a solution of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.9 g) in a mixture of sodium bicarbonate (0.4 g) and water (15 ml). The resulting mixture was stirred for 2 hours under ice-cooling keeping the pH of the mixture at 7.0 to 8.0 and then adjusted to pH 7.5. An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and precipitates were collected by filtration and dried to give 7-[2-(2-propynyl)oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.2 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[S-:18][C:19]#[N:20].[Na+].C(O)C>C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:18][C:19]#[N:20])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (5.7 g) and sodium thiocyanate (5.5 g) were added to ethanol (50 ml), and the mixture was stirred for one hour at 60° C. The reaction mixture was concentrated, and water was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with a solvent mixture of n-hexane:ethyl acetate=10:1 to obtain the desired product (2.2 g, melting point: 129° to 131° C., yield:42%).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[S:27][C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 17): tR=1.42 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: Cl.COCCN(C)C1N=CC(NC(C2N(CC)C3C(C=2)=CC(OC(F)(F)F)=CC=3)=O)=CC=1.Cl.[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:60])[C:39]1[N:44]=[CH:43][C:42]([NH:45][C:46]([C:48]2[N:49]([CH2:58][CH3:59])[C:50]3[C:55]([CH:56]=2)=[CH:54][C:53]([Cl:57])=[CH:52][CH:51]=3)=[O:47])=[CH:41][CH:40]=1.ClC1C=C2C(=CC=1)N(CC)C(C(O)=O)=C2>>[ClH:57].[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:60])[C:39]1[N:44]=[CH:43][C:42]([NH:45][C:46]([CH:48]2[CH:56]=[C:55]3[C:50](=[CH:51][CH:52]=[C:53]([Cl:57])[CH2:54]3)[N:49]2[CH2:58][CH3:59])=[O:47])=[CH:41][CH:40]=1
Reactant: CCn1c(C(=O)Nc2ccc(N(C)CCOC)nc2)cc2cc(Cl)ccc21
Agent: CCn1c(C(=O)Nc2ccc(N(C)CCOC)nc2)cc2cc(OC(F)(F)F)ccc21
Agent: CCn1c(C(=O)O)cc2cc(Cl)ccc21
Agent: Cl
Product: CCN1C2=CC=C(Cl)CC2=CC1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a method similar to that used for the preparation of 1-ethyl-5-trifluoromethoxy-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide hydrochloride, 5-chloro-1-ethyl-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide hydrochloride was prepared from 5-chloro-1-ethyl-1H-indole-2-carboxylic acid. LCMS for C20H23ClN4O2 calcd. (m/e) 386, observed 387 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14](Br)[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(Br)[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cn1
Yield: 88.6 %

Procedure:
(S)-2-[bromo-(6-methoxy-pyridin-3-yl)-methyl]-morpholine-4-carboxylic acid tert-butyl ester (290 mg, 0.75 mmol) was dissolved in methanol (5 mL) and hydrogenated at 0.25 bar in the presence of 50 mg 10% Pd/C. Reaction mixture was diluted with ethyl acetate and filtered through Dicalite. The filtrate was washed with 1M sodium hydroxide. The aqueous phase was extract 2 times with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford (R)-2-(6-Methoxy-pyridin-3-ylmethyl)-morpholine-4-carboxylic acid tert-butyl ester (205 mg, 88%) as a light yellow oil. Chiral HPLC (Chiralpak-AD) indicated that product was 98.3% pure. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.53-2.79 (m, 3H) 2.86-3.00 (m, 1H) 3.38-3.58 (m, 2H) 3.73-3.89 (m, 3H) 3.91 (s, 3H) 6.68 (d, J=8.33 Hz, 1H) 7.39-7.49 (m, 1H) 8.00 (d, J=2.15 Hz, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:43])[C@H:8]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]C(OCC(C)C)C)=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH:1]1([O:6][C:7](=[O:43])[C@H:8]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CCCCCCC(=O)Nc1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1)NO

Procedure:
Material from step 6b (50 mg, 0.083 mmol, 1 eq) was dissolved in DCM/methanol (2 mL:2 mL) and stirred with TFA (1.0 mL) for 2 h. The resulting salt was concentrated, dissolved in methanol and purified by preparative HPLC to yield compound (86). LCMS purity 100%, m/z 502 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.28-1.98 (26H, m, 13×CH2), 2.10-2.15 (2H, m, CH2), 2.40 (2H, t, J=7.8 Hz, CH2), 3.81 (1H, d, J=3.9 Hz, CH), 4.21 (2H, m, CH2), 5.01 (1H, s, CH), 5.23-5.25 (1H, m, CH), 7.43 (2H, d, J=8.4 Hz, Ar—H), 7.68 (2H, d, J=8.7 Hz, Ar—H)
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([C:4]1[C:8]([Cl:13])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: [O-]Cl
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1[nH]nc(C(C)=O)c1Cl
Temperature: 25 °C
Yield: 23 %

Procedure:
Into a flask containing methyl 3-acetyl-1H-pyrazole-5-carboxylate (4.0 g, 0.0238 mol) in acetic acid (60 ml), 5% sodium hypochlorite (284 ml, 0.190 mol) was added dropwise at 10-12° C. The mixture was stirred at RT over three nights adding more 5% sodium hypochlorite (177 ml, 0.119 mol in total) during the second and third day. Water was added to the reaction mixture and the product was extracted with ethyl acetate. Organic layer was dried with anhydrous Na2SO4 and concentrated. The crude product was recrystallized twice from n-hexane. Yield 23%. LC-MS: [M+1]=203.5.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[C:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)#N.N1C=CC=CC=1.C(O)(=[O:35])C>O.[Ni]>[CH:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)(COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The title compound was synthesized by referring to J. Chem. Soc., 1962, 3961. To a solution of sodium hypophosphite monohydrate (1.5 g) in water (3 ml) were sequentially added tert-butyl [2-(4-cyanophenoxy)-1,1-dimethylethyl]carbamate (500 mg), pyridine (10 ml) and acetic acid (5 ml). While stirring at room temperature, Raney nickel (50% suspension in water) (2 ml) was added dropwise to the reaction mixture and the solution was stirred for 15 minutes at room temperature and for 1 hour at 40° C. After filtration through celite pad and several wash with tetrahydrofuran and methanol, the solvent was evaporated in vacuo, and the residue was neutralized by adding a saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the solution was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (443 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrCCCCCBr
Reactant: OCCc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(CCOCCCCCBr)cc1

Procedure:
4-Fluorobenzeneethanol (10.0 g), 1,5-dibromopentane (29 ml), tetra-n-butylammonium hydrogen sulphate (3.2 g, 9 mmol), and aqueous 12.5M NaOH (109 ml) were stirred vigorously at RT overnight. The mixture was diluted with H2O (400 ml), extracted with ER (3×200 ml), and the combined organic extracts were evaporated. The residual oil was purified by [FCS] eluting with CX-ER (100:0→100:6), to give the title compound as a colourless oil (14.37 g). T.l.c. (ER-CX, 19:1) Rf 0.22.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C@H:5]2[C:6](=[O:37])[CH2:7][C@H:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[CH2:10][C@H:9]3[O:32][S:33]([CH3:36])(=[O:35])=[O:34].O>O1CCCC1>[O:3]1[C@H:5]2[CH:6]([OH:37])[CH2:7][C@H:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[CH2:10][C@H:9]3[O:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.42 h

Procedure:
To 1-molar diborane-tetrahydrofuran complex (not stabilized with sodium borohydride, 157 ml) cooled in an ice bath, was added dropwise over about 25 minutes a solution of 1α,2α-epoxy-6β-methylsulfonyloxy-5α-cholestan-25-ol-3-one (20.0 g, 0.392 mole), in tetrahydrofuran (100 ml), with stirring under an atmosphere of nitrogen. After the addition was complete, the solution was stirred for about 25 minutes. Water was cautiously added to the reaction mixture cooled in an ice bath. The mixture was stirred for about 10 minutes and then evaporated at a bath temperature of 35° C in vacuo. The residue was partitioned between methylene chloride and water (ca. 1:1) and the organic layer was separated. The organic phase was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave 1α,2α-epoxy-25-hydroxy-6β-methylsulfonyloxy-5α-cholestan-3-ol, as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of Compound (48a) (30 mg, 0.051 mmol) in 2.0 ml of dry dichloromethane were added 17 μl (0.156 mmol) of anisole and 40 μl (0.51 mmol) of trifluoroacetic acid under ice-cooling, and the mixture stirred for 1 hours at room temperature. Under ice-cooling, an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, which was followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=10:1) to give 24 mg (96%) of Compound (49a).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N+:4]([O-])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C(OCC)(=O)C>CN(C)C=O.CO.[Pd]>[NH2:1][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2ccc(O)cc2[n+]([O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nnc2cc(O)ccc2n1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
4.6 g (25.82 mmol) of 3-amino-benzo[1,2,4]triazine-7-ol-1-oxide was dissolved in 200 mL of 1:1 mixture of dimethylformamide and methanol. 0.5 g of 10% Pd/C was added to this solution and H2 gas was bubbled through the solution for 3 hours. The progress of the reaction was monitored by TLC, using a 9:1 mixture of dichloromethane/methanol as an eluent and a UV lamp. The starting material is highly fluorescent under UV, while the product is not. When the reaction was complete, the resulting dark solution was filtered through a short pad of silica gel and solvent was removed in vacuum to produce a dirty-brown solid. 40 mL of ethyl acetate and 40 mL of methanol were added to the solid and the resulting suspension was heated to reflux for about 10 min. Then the suspension was allowed to cool down to ambient temperature. The solid was collected by filtration, washed with 40 mL of ethyl acetate, 40 mL of diethyl ether and dried in vacuum to yield 3.2 g of the product in a form of a greenish solid. Yield: 76%.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:4](=[O:33])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:47]=1.CCOCC.CCOC(C)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:58]([O:57][C:55]([N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([CH2:45][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:4]2=[O:33])=[N:47]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccs3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccs3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
To a stirring solution of 200 mg (0.43 mmol) of 2-(2,4-dioxo-5-thiophen-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, in 5 mL DMF at 0° C. is added 1.04 mL (0.52 mmol, 1.2 equiv) of NaN(TMS)2 in toluene. The resulting solution is stirred 5 min and 162 mg (0.52 mmol, 1.2 equiv) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added. The resulting solution is stirred 16 h at RT, poured into 100 mL Et2O/EtOAc (1:1), washed with H2O (3×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo to afford 280 mg of the crude title compound: low resolution MS (FAB) m/e 694 (MH+).
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]1)=[O:45].Cl[C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][N:64]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][N:64]=1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 484 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=O)C.C(Cl)Cl.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CO>[CH:4]([C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Yield: 51.8 %

Procedure:
0.50 g (0.0013 mol) of 2-ethoxycarbonyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was dissolved in a solvent mixture comprising 20 ml of methylene chloride and 20 ml of tetrahydrofuran, 2.6 ml of a 1.0 M solution of diisobutylaluminum hydride in toluene was dropped into the solution prepared above at -78° C. under stirring. The obtained mixture was stirred at -78° C. for several hours, followed by the addition of 20 ml of methanol. The obtained mixture was distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate/n-hexane to give 0.23 g of the title compound as a pale-yellow crystal.