Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCO>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[C:15](=[N:2][OH:4])[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(=NO)C(=O)c1c(Cl)cccc1Cl

Procedure:
Slowly bubble N2O3 gas (generated by the dropwise addition of concentrated HCl into an aqueous solution of sodium nitrite) into a stirred solution of ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate (14.4 g, 50 mmol) in EtOH (300 mL) until the reaction is complete (as determined by TLC). Remove the EtOH by evaporation under reduced pressure and partition the residue between EtOAc and water. Dry the organic extract over MgSO4 and evaporate in vacuo to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:22]1[C:31]([C:32]([F:35])([F:34])[F:33])=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:36][CH3:37])[CH:28]=2)[N:23]=1>>[CH3:37][O:36][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=1)[C:31]([C:32]([F:35])([F:33])[F:34])=[N:30]2
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Product: CCOC(=O)C1CC=C(c2nc3ccc(OC)cc3nc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
Followed the coupling procedure similar to that described in Compound VIII-2 (Example 65), where the starting materials were ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and where the reaction here was stirred under N2 atmosphere at 100° C. for 3 hours. Ethyl 4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)cyclohex-3-enecarboxylate was isolated (800 mg, yield 55%) as yellow solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[C:1]1([C:7]#[C:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C#Cc2ccccc2)ccn1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
0.728 mL (6.5 mmol) of phenyl acetylene was added to a mixture of 10.1 g (5 mmol) of 4-bromopicolinic acid, 91 mg (0.13 mmol) of dichlorobis(triphenylphosphine)-palladium(II), 29 mg (0.15 mmol) of copper(I) iodide, 10 mL of triethylamine and 2 mL of DMF and heated at 80° C. overnight. The reaction mixture was filtered. The filtrate was concentrated and partitioned between 5 mL of 2 N Na2CO3 solution, 25 mL of water and 30 mL of ether. The aqueous layer was separated and washed again with ether (30 mL). 10% aq. HCl was added to adjust the pH to 5. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over sodium sulfate. Evaporation of the solvents in vacuo gave 1.028 g (4.61 mmol, 92%) of 4-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224 (M+1)+.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:9][C:8]=2[N+:19]([O-:21])=[O:20])=O.Cl.[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]([NH2:39])[CH2:28][S:29]CC1C=CC(OC)=CC=1>>[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]1[CH2:28][S:29][C:3]([C:5]2[NH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:9][C:8]=3[N+:19]([O-:21])=[O:20])=[N:39]1
Reactant: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Reactant: COC(=O)c1cc2cc(CS(C)(=O)=O)cc([N+](=O)[O-])c2[nH]1
Agent: Cl
Product: COC(=O)C[C@@H]1CSC(c2cc3cc(CS(C)(=O)=O)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
(5-Methanesulfonylmethyl-7-nitro-1H-indol-2-yl)-carboxylic acid methylester prepared in Step A of Preparation 44 and (R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester hydrochloride prepared in Preparation 27 were reacted according to the same procedure as Preparation 40 to give the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.COC1C=C(C=CC=1[N+]([O-])=O)OC1CCNCC1.FC(F)(F)C(O)=O.C=O.COC1C=C(C=CC=1[N+]([O-])=O)OC1CCN(C)CC1.COC1C=C(OC2CCN(C)CC2)C=CC=1N.CS([C:92]1[N:97]=[CH:96][C:95]2=[CH:98][CH:99]=[C:100]([C:101]3[CH:106]=[CH:105][CH:104]=[CH:103][C:102]=3[O:107][CH3:108])[N:94]2[N:93]=1)=O>>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[CH:20]=[CH:19][C:18]=1[NH:21][C:92]1[N:97]=[CH:96][C:95]2=[CH:98][CH:99]=[C:100]([C:101]3[CH:106]=[CH:105][CH:104]=[CH:103][C:102]=3[O:107][CH3:108])[N:94]2[N:93]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: C=O
Agent: COc1cc(OC2CCN(C)CC2)ccc1N
Agent: COc1cc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 16.3 %

Procedure:
Following a procedure analogous to Example 45, 4-(3-Methoxy-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.9 g) was converted to 4-(3-Methoxy-4-nitro-phenoxy)-piperidine as the trifluoroacetic acid salt (3.0 grams) which was converted, using a procedure analogous to 232a, with formaldehyde to 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (76%), which was converted to 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine (100%) using a procedure analogous to 251b, which was converted, using a 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.36 mmol), to the title compound (27 mgs, 16%). H-NMR (CDCl3) δ 8.70 (s, 1H), 8.25 (d, J=10.7 Hz, 1H), 8.03 (d, J=10.7 Hz, 1H), 7.44 (t, J=9.2 Hz, 1H), 7.30 (s, 1H), 7.16-7.02 (m, 3H), 6.85-96.82 (m, 1H), 6.53 (s, 1H), 6.42 (d, J=10.4 Hz, 1H), 4.27 (Broad s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 2.75-2.69 (m, 2H), 2.33 (s, 3H), 2.33-2.26 (m, 2H), 2.04-1.98 (m, 2H), 1.90-1.81 (m, 2H); LC/MS (ESI+): 460 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)[CH3:3].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[O:31])=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1ccc(SC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of 9-{[4-(1-methylethyl)phenyl]sulfanyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (137.4 mg) in dehydrated DMF (3 mL) was added a mixture of 3-chloroperbenzoic acid (75%, 99 mg) in dehydrated DMF (3 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (67.6 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1cncc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cncc(-c2ccccc2)c1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 419 mg of 2-[1-(3-phenyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 18), 585 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 429 mg of triphenylphosphine and 285 mg of diethyl azodicarboxylate, 522 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:50]([S:53]([CH2:56][CH2:57][NH2:58])(=[O:55])=[O:54])[CH2:51][CH3:52]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:58][CH2:57][CH2:56][S:53]([CH2:50][CH2:51][CH3:52])(=[O:55])=[O:54])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CCCS(=O)(=O)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)CCNC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Yield: 18.3 %

Procedure:
Prepared according to Procedure I utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.23 g, 0.42 mmol), carbonyldiimidazole (0.21 g, 1.27 mmol), and n-propanesulfonylethylamine (0.16 g, 0.85 mmol) in DMF to afford the title compound (0.05 g) after purification by chromatography. Electrospray MS m/z 649 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3cccc(C#N)c3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-bromomethyl benzonitrile, whereby the product was isolated as free base, 3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a yellow solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1>CC#N>[CH2:9]([O:8][C:7]([NH:6][C@@H:5]([CH2:4][N:17]1[CH:21]=[CH:20][CH:19]=[N:18]1)[C:2]([OH:3])=[O:1])=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cn[nH]c1
Reactant: O=C(N[C@H]1COC1=O)OCc1ccccc1
Solvent: CC#N
Product: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Temperature: 50 °C
Yield: 37.7 %

Procedure:
A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03 mmol), and pyrazole (0.22 g, 3.29 mmol) in CH3CN (12 mL) was heated at 50° C. for 24 h. The mixture was cooled to rt overnight and the solid filtered to afford (S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1 mg). The filtrate was concentrated in vacuo and then triturated with a small amount of CH3CN (ca. 4 mL) to afford a second crop (43.5 mg). Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5 [Vederas et al. J. Am. Chem. Soc. 1985, 107, 7105]. 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66 (m, 2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. for C14H15N3O4: 289; found: 290 (M+H)+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2(O)[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.BrC1C=CC(C2CCN(C)CC=2)=CC=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([F:7])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCC(O)(c2ccc(Br)cc2)CC1
Agent: CN1CC=C(c2ccc(Br)cc2)CC1
Solvent: ClCCl
Product: CN1CCC(F)(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of DAST (0.50 g, 3.8 mmol) in CH2Cl2 was added a solution of 4-(4-bromophenyl)-1-methylpiperidin-4-ol (0.507 g, 1.88 mmol) in CH2Cl2 at −78° C. The resulting mixture was warmed to rt over a period of 3 h. The reaction was then allowed to cool to 0° C. and quenched with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4 and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (95:5 EtOAc/NH3 to 10:8:2 CH2Cl2/MeOH/NH3) to yield an inseparable mixture of the title compound and 4-(4-bromophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (280 mg, used without further purification).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].C(Cl)Cl.C(O)(=O)C1C(=CC=CC=1)O>C1(C)C=CC=CC=1>[NH:18]1[C:1]([CH:3]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4]2)=[N:2][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)C1
Agent: O=C(O)c1ccccc1O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)C1
Temperature: 115 °C
Reaction time: 5 h
Yield: 910 %

Procedure:
To a solution of benzyl 3-cyanopyrrolidine-1-carboxylate (1.0 g) and TEA hydrochloride (2.99 g) in toluene was added sodium azide (1.41 g) at 25° C., followed by stirring at 115° C. for 5 hours. The reaction liquid was left to be cooled and DCM (10 mL) was added thereto. Then, to a 5% aqueous salicylic acid solution (100 mL) was added dropwise the reaction liquid, followed by stirring at 25° C. for 1 hour. The reaction liquid was extracted with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain benzyl 3-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylate (10.8 g) as a colorless liquid.
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:23]([N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:38][CH:39]=1)[CH3:31])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Product: CN(Cc1ccccc1)Cc1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26]C(C)([O-])C.[K+].CI>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:26])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COc1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reaction time: 0.08 h
Yield: 14.9 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 13) (73 mg, 0.20 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (21 mg, 0.187 mmol). The reaction was stirred for 5 min before adding methyl iodide (0.012 mL, 0.201 mmol, Aldrich). The reaction was stirred at ambient temperature, overnight and under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound (10.5 mg); LCMS: (System 4) MH+=378, tRET=2.86 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][C:17]#[CH:18])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[N:10]([CH2:16][C:17]#[C:18][I:20])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN1C(=O)N(Cc2ccccc2)C(=O)C1(C)C
Reactant: O=C1CCC(=O)N1I
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C)C(=O)N(Cc2ccccc2)C(=O)N1CC#CI
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
To a solution of 3-benzyl-1-propargyl-5,5-dimethylhydantoin (2 g, 7.81 mmole) in acetone (35 mL) at room temperature was added N-iodosuccinimide (2.1 g, 9.2 mmole), followed by silver nitrate (0.265 g, 1.56 mmole). The reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was then passed through Celite by suction-filtration and washed with acetone. The filtrate was concentrated on a rotary evaporator and diluted with ethyl acetate. The solution was washed with water and brine and dried over sodium sulfate. The solvent was evaporated on a rotary evaporator to give 1.9 g of 3-benzyl-1-(3-iodo-2-propynyl)-5,5-dimethylhydantoin as a light brown oil which slowly solidified, mp=83°-85° C. An NMR spectrum also showed the desired structure.
Reaction SMILES: N[C:2]1[C:3]2[C:12]3[CH:13]=[N:14][N:15]([CH2:16][CH3:17])[C:11]=3[N:10]=[CH:9][C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.N([O-])=[O:19].[Na+].S(=O)(=O)(O)O.[N]=O.[N+]([O-])=O>O>[CH2:16]([N:15]1[C:11]2[N:10]=[CH:9][C:4]3[C:5](=[O:8])[NH:6][NH:7][C:2](=[O:19])[C:3]=3[C:12]=2[CH:13]=[N:14]1)[CH3:17]
Reactant: CCn1ncc2c3c(N)n[nH]c(=O)c3cnc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+][O-]
Agent: [N]=O
Solvent: O
Product: CCn1ncc2c3c(=O)[nH][nH]c(=O)c3cnc21
Temperature: 25 °C

Procedure:
To a suspension of 9-amino-3-ethyl-3H-pyrazolo[4′,3′:5,6]pyrido[3,4-d]pyridazin-6(7H)-one (5.0 g, 21.7 mmol) and sodium nitrite (15.0 g, 10 eq) in water (200 mL) was added concentrated sulfuric acid until the pH was <2. The suspension was stirred vigorously and some nitric oxide—nitrogen dioxide was evolved. This suspension was then placed on a hot plate and heated to boiling. The pH of the reaction was maintained at pH>2 with the addition of sulfuric acid as necessary. When the reaction was judged complete by HPLC, the resulting reaction mixture was cooled to rt. The precipitated white solid was collected by filtration, washed with water thoroughly and dried under vacuum to afford the title compound as an off white solid (4.6 g, 92%, purity >95% as judged by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:27])[CH2:25][CH3:26])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCC(=O)O
Product: CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and propionic acid to yield (3aR,4S,7aR)-4-propionyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.34 min; UPLC Method I
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=CC(S(N[C@H]2CC[C@H](C(OC)=O)CC2)(=O)=O)=CC=1[N+]([O-])=O>>[CH2:15]([NH:22][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1
Agent: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Product: O=S(=O)(NCc1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
4-(Trifluoromethyl)benzene-1-sulfonyl chloride (1 gm) was coupled to benzylamine using conditions analogous to those used to prepare intermediate 1. Purification by chromatography yielded N-benzyl-4-(trifluoromethyl)benzenesulfonamide (770 mg). Rf=0.38 by TLC eluting with 30% ethyl acetate in heptane. MS MH+ 316.2
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Cl:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O.O>[ClH:15].[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1nc2ccccc2s1
Temperature: 95 °C

Procedure:
11.8 g phenylalanine (73.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95° C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.