Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)=[CH:4][CH:3]=[N:2]1.O[C@H:19]([CH3:29])[CH2:20][NH:21]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[NH2:21][CH2:20][C@@H:19]([N:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=2)=[N:1]1)[CH3:29]
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared from 4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrile (1.4 g, 5.90 mmol), (R)-tert-butyl 2-hydroxypropylcarbamate (1.03 g, 5.90 mmol), triphenylphosphine (2.32 g, 8.85 mmol) and di-tert-butyl azodicarboxylate (2.04 g, 8.85 mmol) using the method of Example 34(c). Yield 0.429 g. 1H NMR (400 MHz; MeOD): δ 1.52 (d, 3H), 2.98 (dd, 1H), 3.12 (dd, 1H), 4.43 (m, 1H), 6.87 (d, 1H), 7.77 (d, 1H), 7.98 (m, 1H), 8.21 (m, 1H), 8.33 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of methanol was dissolved 24.5 g of 3,5-bistrifluoromethylbenzaldehyde, and under ice-cooling, added thereto was 60 ml of ethylamine (a 2M tetrahydrofuran solution). Subsequently, 4.38 g of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added distilled water and concentrated under reduced pressure. The residue was extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→chloroform:methanol=9:1), to give 6.35 g of N-(3,5-bistrifluoromethylbenzyl)-N-ethylamine as shown in Table 135 below.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCCCCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=[C:21]([Br:24])[Br:20])=[CH:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1cc(C=C(Br)Br)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Triphenylphosphane (17.2 g, 65.5 mmole) was added in portions at 0° C., while stirring and within 60 min to a solution of tetrabromocarbon (10.9 g, 32.7 mmole) in DCM (120 ml) and post-stirred for 1 h at 0° C. 3-formyl-indole-1-carboxylic acid-tert-butylester (4 g, 16.4 mmole) dissolved in DCM (30 ml) was subsequently added dropwise within 30 min and the mixture stirred for 4 h at 0° C. After heating the solution to RT, hexane (300 ml) was added and the mixture stirred for 30 min at RT. The mixture was suction filtered and post-washed with hexane. The filtrate was evaporated, a yellow solid being obtained. Chromatographic purification on silica gel was carried out using cyclohexane/EE (95:5). 6.26 g 3-(2,2-dibromovinyl)-indole-1-carboxylic acid-tert-butylester were obtained (white solid, mp. 101 to 104° C.). A solution of 3-(2-2,-dibromovinyl)-indole-1-carboxylic acid-tert-butylester (2.97 g, 7.4 mmole) in THF (20 ml) was introduced at −78° C. under argon, and subsequently a 1.6 M solution of n-butyllithium in hexane (5.7 ml, 9.1 mmole) was added within 30 min, the mixture stirred for 1 h at −78° C., brought to room temperature and then added to a solution, cooled to −78° C., of 4-dimethylamino-4-phenylcycohexane carbaldehyde (580 mg, 2.5 mmole) in THF (10 ml). The mixture was stirred for 8 h at −78° C., brought to room temperature and water (20 ml) was added. For working up, the aqueous phase was extracted with toluene (3×15 ml). The combined organic phase was washed with saturated NH4Cl, 0.2M NaOH and water (about 20 ml in each case), dried over sodium sulfate, filtered and evaporated. First chromatographic purification of the substance mixture obtained was carried out using acetonitrile/methanol/1M NH4Cl (9:1:1) on silica gel. Three compounds were obtained following a second column chromatographic separation with methanol on silica gel:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:11])[CH2:10][S:9]1.O>C1C=CC=CC=1>[CH3:7][C:8]([SH:9])([CH3:11])[CH2:10][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC1(C)CS1
Reactant: C1CNCCN1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(S)CN1CCNCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Piperazine (7.72 g, 89.8 mmol) was dissolved in benzene (10 mL) and 2,2-dimethylthiirane (3.16 g, 35.9 mmol) was added. The reaction mixture was stirred at 80° C. for 1 hour, poured into the water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 3.9 g of the title compound. 1H NMR (CDCl3, 300 MHz): δ1.29 (s, 6H), 2.34 (s, 2H), 2.58 (t, 4H), 2.63 (s, 1H), 2.85 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]O.S(=O)(=O)(O)O>O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 50 g of 3-chloro-4-hydroxybenzeneacetic acid, 250 ml of methyl alcohol and 10 ml of concentrated sulfuric acid is heated at reflux temperature for 23.5 hours. The cooled solution is diluted with water and extracted with methylene chloride. The organic layer is washed with saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:30% ethyl acetate/hexane) to give 49.9 g of the desired product.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[OH:41][NH2:42]>CCO>[NH2:32][C:31](=[N:42][OH:41])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2

Procedure:
To a suspension of 18.2 g of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-6-cyano-spiro[chroman-2,4′-piperidine]-1′-carboxylate in EtOH was added 16.3 mL of Et3N and 8.12 g of hydroxyamine hydrochloride at rt, and the reaction mixture was stirred at 85° C. for 1d. The resultant solution was cooled to rt, and concentrated in reduced pressure. To the residue was added H2O, the resultant white solid was filtered, washed with H2O, and dried in vacuo to give a crude product, which was used in the next step without further purification.
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=1>>[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])=[CH:58][CH:57]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Reactant: Fc1ccc(CBr)cc1
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 71 %

Procedure:
(S)-1-(4-Fluorobenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18e) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-fluorobenzyl bromide, and purified with hexanes-ether (1:2) to afford 85 mg (71%) of 18e as an orange solid, mp 164.6-165.7° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8 Hz, 1H), 7.97 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.34-7.20 (m, 4H), 7.07 (t, J=8.7 Hz, 2H), 6.94 (t, J=7.2 Hz, 1H), 6.86-6.77 (m, 3H), 4.90 (s, 2H), 4.47 (m, 1H), 4.10 (m, 2H), 3.85 (m, 2H), 2.36-2.22 (m, 2H). Anal. Calcd for C25H21FN2O5S: C, 62.49, H, 4.41; N, 5.83. Found: C, 62.27, H, 4.48; N, 5.69.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH:27]=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:18][NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:3][CH3:1])=[CH:9][CH:8]=2)[C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=CNc1ccc(C(c2ccc(NC=O)cc2)c2ccc(NC=O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(C(c2ccc(NC)cc2)c2ccc(NC)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.3 %

Procedure:
The tris(4-formylaminophenyl)methane (130 mg) obtained in Reference Example 31 was dissolved in tetrahydrofuran (5 ml), after which lithium aluminum hydride (66.1 mg) was added under a nitrogen atmosphere at 5° C., the temperature was raised to room temperature, and the mixture was stirred for 19 hours. Water (5 ml) was added to the reaction mixture at 5° C., and stirring was continued for 10 minutes. The reaction mixture was filtered with celite and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (Kiesel-gel 60, 240-400 mesh) and elution was performed with a mixed solvent of chloroform:methanol=98:2 to obtain 81.1 mg of the title compound as a yellow oily substance (70% yield).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([OH:10])[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:10][C:8]1[N:7]([C:11](=[O:14])[NH:12][CH3:13])[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:9]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNC(=O)n1nc(C(C)(C)C)nc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNC(=O)n1nc(C(C)(C)C)nc1OCc1ccccc1
Yield: 3.5 %

Procedure:
To a mixture of 3-tert-butyl-1-N-methylcarbamoyl-5-hydroxy-1,2,4-triazole 5.94 g (0.03 mole) and potassium carbonate 6.21 g (0.045 mole) was added 100 ml of methyl-ethyl ketone. Then to the mixture was added, while stirring, 4.17 g (0.033 mole) of benzyl chloride, and the mixture was heated under reflux for 2 hours. After the reaction mixture was concentrated under a reduced pressure, the residue obtained was diluted with water and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure, and the pale yellow oily substance obtained was subjected to silica gel column chromatography and eluted with a solvent mixture of 1:2 of ethyl acetate and n-hexane, to give 0.3 g of 5-benzyloxy-3-tert-butyl-1-N-methylcarbamoyl- 1,2,4-triazole as a white solid (yield 3.5%).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[C:34](=[CH:45][CH:46]=1)[C:35](OCC1C=CC=CC=1)=[O:36]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:48](=[O:49])[NH:47]2)=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: COc1ccc(C(=O)OCc2ccccc2)c(NC(=O)Oc2ccccc2)c1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C(=O)O)c(N)c3)c(=O)[nH]c2c1
Yield: 3.1 %

Procedure:
500 mg (1.23 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg (1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 15 mg (yield 3.1%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.82 (3H, s), 6.58 (1H, s), 6.80 (1H, d), 7.16 (1H, d), 7.56 (1H, s), 7.80 (1H, d), 7.90 (1H, d), 11.49 (1H, s).
Reaction SMILES: C([O:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][CH:11]2[NH:20][C:19](=[O:21])[NH:18][CH:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C(C)(C)C)=[CH:25][CH:24]=3)[CH:16]3[CH:12]2[O:13]C(C)(C)[O:15]3)=[CH:8][CH:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[OH:13][CH:12]1[CH:16]([OH:15])[CH:17]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)[NH:18][C:19](=[O:21])[NH:20][CH:11]1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:37][CH:36]=1
Reactant: CC(C)(C)Oc1ccc(CC2NC(=O)NC(Cc3ccc(OC(C)(C)C)cc3)C3OC(C)(C)OC23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(Cc2ccc(O)cc2)C(O)C(O)C(Cc2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclic Urea 2.8 (0.4 g, 0.78 mmol) was dissolved in dichloromethane (3 mL) and treated with TFA (1 mL). The mixture was stirred at room temperature for 2 h upon which time a white solid precipitated. 2 drops of water and methanol (2 mL) were added and the homogeneous solution was stirred for 1 h and concentrated under reduced pressure. The crude solid, 2.9, was dried overnight and then used without further purification.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)CCl.[C:25]([CH:27]=[P:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH: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)#[N:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][C:11](=[O:12])[NH:10][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7](=[O:9])[C:27]([C:25]#[N:26])=[P:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
This intermediate was prepared generally according to the method of Wasserman et al., J. Org. Chem. (1994), vol. 59, 4364. In particular, to a solution of (3-acetylamino-2-benzyloxycarbonylaminopropionic acid (1.40 g, 5.0 mmol, 1 equiv) in CH2Cl2 (50 mL) at 0° C. were added EDC (1.00 g, 5.25 mmol, 1.05 equiv) and DMAP (61 mg, 0.5 mmol, 0.1 equiv). A solution of (cyanomethylene)triphenylphosphorane (prepared as described in Freudenreich et al., J. Am. Chem. Soc. (1984), vol. 106, 3344) (2.50 g, 8.30 mmol, 1.66 equiv) in CH2Cl2 (16 mL) was added to the acid solution dropwise over 20 min. After stirring 2 h at 0° C., the reaction mixture was partitioned between deionized water (30 mL) and CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (5% CH3OH in CH2Cl2) to give [1-(acetylaminomethyl)-3-cyano-2-oxo-3-(triphenyl-λ5-phosphanylidene)propyl]-carbamic acid benzyl ester (1.98 g, 70% yield) as a colorless foam. Rf=0.40 (10% CH3OH in CH2Cl2). IR (cm−1) 3312, 2175, 1716, 1437. 1H NMR (CDCl3) δ1.91 (s, 3H), 3.66-3.79 (m, 2H), 5.04-5.06 (m, 1H), 5.10 (s, 2H), 5.94 (br s, 1H), 6.21 (br s, 1H), 7.26-7.70 (m, 21H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[CH2:18]([Mg]Br)[CH3:19].C(I)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH3:19])#[N:2]
Reactant: CC[Mg]Br
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c[nH]c2ccc(-c3ccccc3C#N)cc12
Yield: 31.6 %

Procedure:
5-(2-cyanophenyl)indole (1.26 mmoles, 630 mg) was dissolved in THF (20 ml) and treated with ethylmagnesium bromide (1.26 mmoles, 0.630ml) and ethyl iodide (3.45 mmoles, 0.54 g) as in Example 24 to yield 98 mg of 5-(2-cyanophenyl)-3-ethylindole. (MS)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:34]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:4]3[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)[CH3:33]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Reactant: CCC(N)=NO
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 67 mg (0.75 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 17 mg (7% of theory).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15](/[N:17]=[C:18](\OC1C=CC=CC=1)/[NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)#[N:16]>C(O)(C)C>[CH:32]1([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:18]4[N:17]=[C:15]([NH2:16])[N:1]([C:3]5[N:8]=[N:7][C:6]6[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=6[CH:4]=5)[N:2]=4)=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: NNc1cc2c(nn1)CCCCCC2
Reactant: N#C/N=C(/Nc1ccc(N2CCN(C3CCCCC3)CC2)cc1)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCN(C4CCCCC4)CC3)cc2)nn1-c1cc2c(nn1)CCCCCC2

Procedure:
3-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine (101 mg, 0.53 mmol) and (Z)-phenyl N′-cyano-N-(4-(4-cyclohexylpiperazin-1-yl)phenyl)carbamimidate (212 mg, 0.53 mmol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). A portion of the crude product was purified by C-18 reversed phase hplc to give N3-(4-(4-cyclohexylpiperazin-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydrocycloocta[c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine, compound #16, 17 mg. 1H NMR (CDCl3, 300 MHz) 8.41 (s, 1H), 7.55 (d, 2H), 6.92 (d, 2H), 3.38 (m, 3H), 3.15 (m, 6H), 2.96 (m, 1H), 2.80 (m, 2H), 2.11 (m, 2H), 1.67-1.90 (m, 7H), 1.05-1.45 (m, 10H) ppm; MS (ES) 502.28 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=O.Cl>>[Cl:15][CH:16]([Cl:20])[C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Product: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 17.44 g of 2-amino-3-trifluoromethylbenzoic acid prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106 and 34.63 g of dichloroacetyl chloride was progressively heated with stirring and at about 50° C., a hardening of the mass with rapid gas evolution of regular hydrogen chloride occured for one hour. Towards 100° C., one observed a fluidization of the reaction mixture, an intensification of hydrogen chloride evolution and an increase in the temperature of 127° C. The heating was continued until hydrogen chloride evolution ceased to obtain a brown solution which was cooled in an ice bath with stirring. The mixture was vacuum filtered and the product was empasted with ether, then with methanol and was washed with methanol to obtain 23.82 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)nc(Cl)c1
Yield: 101.1 %

Procedure:
Oxidation of the above alcohol (1.2 g) according to the conditions of Swern (oxalyl chloride, 0.33 ml; dimethyl sulphoxide, 0.54 ml; triethylamine, 2.35 ml) gave (2,6-dichloro-4-pyridyl)methanal (1.2 g). NMR 1H: 10.02(1H,s), 7.68(2H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34](=[O:44])[C:35](=[O:43])[N:36]2[CH2:39][C:40](O)=[O:41])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:38]=2)[C:34](=[O:44])[C:35]1=[O:43]
Reactant: COc1ccc2c(c1)N(CC(=O)O)C(=O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C(=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), 2-(6-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature for 4 hours; then the reaction mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.166 g, 0.260 mmol, 55% yield). MS/ESI+ 637.19 [MH]+; [αD]=+67.91 c=0.22 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 7.61 (d, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 6.94 (dd, 1H), 7.07 (t, 1H), 6.69 (dd, 1H), 6.66 (d, 1H), 6.02 (dd, 1H), 4.60 (s, 2H), 3.89 (d, 2H), 3.86 (s, 3H), 3.38 (dd, 1H), 3.19 (dd, 1H), 1.07-1.33 (m, 1H), 0.48-0.67 (m, 2H), 0.18-0.48 (m, 2H)