Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10](O)=[N:9][C:8]2=[O:14])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[N:11]=[CH:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:14])[N:9]=1
Reactant: O=c1nc(O)ncn1Cc1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A toluene solution (25 mL) of 1-(4-chlorobenzyl)-4-hydroxy-1,3,5-triazin-2(1H)-one (600 mg, 2.52 mmol) synthesized in Reference Synthesis Example 10, N,N-diisopropylethylamine (0.52 mL, 4.63 mmol), and phosphorus oxychloride (0.94 mL) was stirred at 70° C. for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and toluene was added, followed by concentrating the resultant mixture under reduced pressure again. To the obtained crude product of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one, chloroform was added and the resultant solution was used in the next reaction as the chloroform solution.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2C=[C:30]3[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)[CH2:12][CH2:11]1)[CH3:2].[Na+].[I-].Cl.C(OC1C=CC=CC=1[N:45]1CCCNCC1)C.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[N:45]=[C:30]3[C:25]([CH2:26][CH2:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOc1ccccc1N1CCCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Reactant: CCOc1ccccc1N1CCCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CCOc1ccccc1N1CCCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of intermediate 12 (150 mg, 0.48 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 31 (124 mg, 0.48 mmol) and anhydrous K2CO3 (265 mg, 1.92 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-(4-(4-(2-ethoxyphenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (compound 13) (50 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 7.55 (bs, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.89-6.85 (m, 4H), 6.34 (d, J=8.1 Hz, 1H), 4.24-4.20 (m, 2H), 4.04 (q, J=6.9 Hz, 2H), 3.41-3.37 (m, 2H), 3.31 (t, J=5.7 Hz, 2H), 3.15-2.95 (m, 4H), 2.86 (t, J=6.9 Hz, 2H), 2.79-2.69 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.20-2.12 (s, 2H), 1.82-1.76 (m, 4H), 1.45 (t, J=6.9 Hz, 3H). HPLC: 99%, RT 2.393 min. MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15]CC)=O)=[CH:7][N:6]([CH3:18])[C:5]=2[C:4]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C[O-].[Na+]>CO>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:13]([C:8]2[C:9](=[O:12])[C:10]3[S:11][C:3]([CH2:2][OH:1])=[C:4]([CH3:19])[C:5]=3[N:6]([CH3:18])[CH:7]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn(C)c2c(C)c(CO)sc2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of ethyl 2-(hydroxymethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (627 mg, 2.23 mmol), 4-chlorobenzylamine (2.0 mL, 16.4 mmol), 0.5 M sodium methoxide in methanol (25 mL, 8.92 mmol) and methanol (10 mL) was stirred under nitrogen in a tightly capped 250 mL round bottom flask at 50° C. for 24 hours. The initial solution slowly dropped a thick white precipitate during the reaction. After cooling to room temperature, the mixture was filtered, and the collected solid was washed with methanol and dried in vacuo, leaving a white solid. The crude solid was suspended in boiling methanol (200 mL), cooled to room temperature, and filtered, to give the title compound as a white powder (585 mg).
Reaction SMILES: [NH2:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)=[C:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41]([NH:1][C:2]3[C:22]([O:23][CH3:24])=[CH:21][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]5[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]5)=[O:13])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:40]=2)=[C:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])[CH:31]=1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(Cl)cc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.025 g, 20%). MP: 137-150° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.21 (s, 1H), 8.46 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J=2.5 Hz), 7.51-7.47 (m, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 3.75-3.63 (m, 4H), 3.30 (s, 2H), 2.91-2.86 (m, 2H), 2.77 (s, 6H), 2.76-2.63 (m, 6H), 2.49-2.38 (m, 4H), 2.33 (s, 3H). MS: 677.18 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([S:21][CH2:22][C:23](=O)[CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:23]([CH3:24])[CH2:22][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CSc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CSc1ccccc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-phenylsulfanyl-propan-2-one.
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][OH:9].[CH2:10]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:20])[N:19]=1)[C:15]#[N:16])[CH3:11]>CO>[CH2:10]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:20])[N:19]=1)[C:15]([NH:8][OH:9])=[NH:16])[CH3:11]
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)n1
Yield: 108.3 %

Procedure:
At 0° C., KOtBu (1.81 g, 16.2 mmol) is carefully added to methanol (25 mL). Hydroxylamine hydrochloride (963 mg, 13.9 mmol) is then added to this solution. The suspension is stirred for 30 min before 2-ethyl-6-methyl-isonicotinonitrile (675 mg, 4.62 mmol) is added. The mixture is refluxed for 1 h, the solvent is evaporated. The residue is dissolved in water, extracted three times with EA. The org. extracts are dried over MgSO4, filtered, evaporated and dried under HV to give 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine (897 mg) as a white powder, LC-MS: tR=0.31 min, [M+1]+=180.32.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)c1ccccc1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-1-benzoyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 466.2 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([OH:24])[C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)(=O)=O)=CC=1.[OH-].[K+]>C1COCC1>[O:24]1[CH2:12][C@H:13]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(C(F)(F)F)nc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@@H]2CO2)cn1
Reaction time: 0.67 h

Procedure:
To a stirred solution of (R)-2-hydroxy-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.0 g, 2.77 mmol) in THF (50 mL) was added powder potassium hydroxide (464 mg, 8.28 mmol) in small portions. The mixture was stirred for 40 minutes and TLC indicated completion of the reaction. The mixture was filtered through Celite and the filter cake was washed with acetonitrile (50 mL). The filtrate was carefully concentrated to a half volume and the obtained expoxide solution was used directly for the next step reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.[I:29]I.OS([O-])=O.[Na+]>C1COCC1.O.C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[I:29]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccn1
Agent: CN(C)CCN(C)C
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
An oven-dried 3-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with tert-butyl (4-fluoropyridin-2-yl)carbamate (Int-26, 31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to −78° C. and a solution of n-butyllithium (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise such that the reaction mixture temperature remained below −70° C. Upon completion of addition, the reaction mixture was stirred at −78° C. for 1 h, and a solution of I2 (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was again controlled to keep the reaction mixture temperature below −70° C., and the resulting mixture was stirred at −78° C. for 1 h. A solution of NaHSO3 (61 g, 580 mmol) in water (200 mL) was added to the reaction mixture as it warmed to room temperature. Ethyl acetate was added and the biphasic mixture was stirred at room temperature for 1 h. Water (500 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3×400 mL); the organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give an off-white solid. This solid was suspended in methylene chloride (50 mL) and the solid was isolated by suction filtration and washed with a minimum of methylene chloride. The filtrate was concentrated and filtered to give a second crop of product. The solids were combined and dried under vacuum to give tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate as a white solid (45.63 g, 86% yield). LC-MS: (FA) ES+ 339. 1H NMR (400 MHz, d6-DMSO) δ ppm 9.47 (s, 1H), 8.32 (dd, J=8.9, 5.5 Hz, 1H), 7.18 (dd, J=7.2, 5.5 Hz, 1H), 1.44 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1.[C:16]1([NH:22][C:23]([C:25]2[N:26]=[C:27]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]3[CH:36]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:14][C:10]1[N:9]=[C:8]([C:30]2[CH:31]=[CH:32][C:27]3[N:28]([CH:36]=[C:25]([C:23]([NH:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:24])[N:26]=3)[CH:29]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(B(O)O)ccc2n1
Reactant: COc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)n1
Yield: 21.8 %

Procedure:
To a solution of 624 mg of caesium carbonate, 90 mg of 2-bromo-6-methoxypyridine and 17.5 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium in 10 mL of dioxane and 4 mL of water are added 160 mg of 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-boronic acid. The mixture is refluxed for one hour, and then cooled and concentrated to dryness under reduced pressure. The residue is taken up in 150 mL of dichloromethane and washed with 100 mL of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure on silica and then chromatographed on a silica cartridge, eluting with a gradient of from 0 to 35% ethyl acetate in cyclohexane. The fractions containing the pure expected product are combined and concentrated to dryness under reduced pressure to give 36 mg of 6-(6-methoxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([NH2:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([NH2:33])[CH3:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(N)c1ccc(Br)cc1
Product: CC(N)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available (rac)-4-bromo-alpha-methylbenzyl amine (0.14 mL, 1.0 mmol) according to general procedure II. Obtained as an orange solid (200 mg, 42%). MS (ISN) 533.1 [(M−H+OAc)−]; mp 156-157° C.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[S:19])[N:17]([CH3:20])[N:16]=[C:15]1[C:21]([F:24])([F:23])[F:22]>Cl.O.[Fe]>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]([N:14]2[C:18](=[S:19])[N:17]([CH3:20])[N:16]=[C:15]2[C:21]([F:23])([F:22])[F:24])=[C:5]([Cl:4])[CH:10]=1
Reactant: Cn1nc(C(F)(F)F)n(-c2ccc([N+](=O)[O-])cc2Cl)c1=S
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1nc(C(F)(F)F)n(-c2ccc(N)cc2Cl)c1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a stirred mixture of 18.8 g (0.0337 mole) of iron powder in 400 ml of concentrated hydrochloric acid, 20 ml of water, and 300 ml of ethanol was added slowly 28.5 g of 4-(2-chloro-4-nitrophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione. This mixture was heated at reflux for eight hours and then was cooled to room temperature and stirred for approximately 18 hours. The mixture was heated to reflux and was filtered hot. The filter cake was washed with methylene chloride. The wash and the filtrate were combined, and the solvents were removed by evaporation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with diethyl ether to yield 23.4 g of 4-(4-amino-2-chlorophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as a solid, mp 145°-147° C., Compound 94 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]#[C:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH3:18].[Li].N>>[CH2:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]#[C:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCC/C=C/CCCC
Reactant: OCCCCCCBr
Agent: N
Agent: [Li]
Product: CCCC/C=C/CCC#CCCCCCCO

Procedure:
The use of a protected derivative of 6-bromohexanol can be avoided. Thus, an excess of lithium (E)-5-decen-1-yne in liquid ammonia is used and allowed to react directly with 6-bromohexanol to give (E)-11-hexadecen-7-yne-1-ol, bp 134°-136°/1 mm, nD21 1,4755. Acetylation converts the alcohol to the above acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(C(C)C)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: CC(C)c1ccc(-n2cc[nH]c2=O)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: CC(C)c1ccc(-n2ccn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Product: CC(C)c1ccc(-n2ccnc2O[C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)cc1
Yield: 13.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.83 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.83 g of 1-(4-isopropylphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-isopropylphenyl)-2(1H,3H)-imidazolone (0.25 g) and 0.22 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-isopropylphenyl)-2-imidazolyloxy]ethyl] oxiran were obtained.
Reaction SMILES: C[Al](C)C.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH2:15].C[O:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[C:25]([C:29]3[C:34]([Cl:35])=[CH:33][C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][C:30]=3[Cl:42])[NH:26]2)=[CH:22][CH:21]=1)=O.C[Al](C)C.N1C2C(=CC=CC=2)C=CC=1N>C1(C)C=CC=CC=1>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[C:25]([C:29]3[C:30]([Cl:42])=[CH:31][C:32]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:33][C:34]=3[Cl:35])[NH:26]2)=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cc(N4CCOCC4)cc3Cl)[nH]c2c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cc(N4CCOCC4)cc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A 2 M solution of AlMe3 in toluene (0.74 mL, 1.48 mmol) was added to a flask charged with dry toluene (6 mL) at 0° C. under N2. In one proportion quinolin-2-ylamine (0.213 g, 1.48 mmol) was added and the mixture was allow to stir for 50 min. The reaction was allowed to warm to ambient temperature over 15 min then a suspension of 2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-1H-indole-6-carboxylic acid methyl ester (0.500 g, 1.23 mmol) in toluene was slowly added to the mixture at 0° C. Upon completing the addition the mixture was heated at 100° C. After 20 h an additional portion of AlMe3/quinolin-2-ylamine solution (0.438 mmol) was added and heating was continued for an additional 3 h. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was partitioned between EtOAc (70 mL) and 1 N HCl (30 mL) and allowed to stir for 1 h. The resulting precipitate was filtered and dried under reduced pressure to afford 2-(2,6-dichloro-4-morpholin-4-yl-phenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 11.26 (s, broad, 1H), 8.50 (d, J=8.97 Hz, 1H), 8.34 (d, J=8.97 Hz, 1H), 8.20 (s, 1H), 8.00 (d, J=8.21 Hz, 1H), 7.97 (d, J=8.46 Hz, 1H), 7.76-7.82 (m, 2H), 7.68 (d, J=8.34 Hz, 1H), 7.57 (t, J=7.45 Hz, 1H), 7.17 (s, 2H), 6.54 (d, J=1.77 Hz, 1H), 3.71-3.77 (m, 4H), 3.24-3.32 (m, 4H). MS (m/z) 517.1 (M+1).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:8][CH2:7][C:6]2([CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]2)[CH2:5]1.Cl.O>C(#N)C>[CH2:5]1[C:6]2([CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]2)[CH2:7][CH2:8][CH:4]1[CH:3]=[O:2]
Reactant: COC=C1CCC2(CCC=CCC2)C1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=CC1CCC2(CCC=CCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.3 %

Procedure:
To a solution of the crude 2-(1-methoxymethylidene)spiro[4.6]undec-8-ene (900 mg) obtained in Step 4 in acetonitrile (10 mL) was added 1N aqueous hydrochloric acid solution (2 mL), followed by stirring at room temperature for 4 hours. Then, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel to give spiro[4.6]undec-8-ene-2-carbaldehyde (44 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14])=[N+]=[N-].[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of 1-[4-[2-(2-azidomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (535 mg) in a mixture of methanol (35 ml) and dioxane (4 ml) containing catalytic palladium on carbon (60 mg) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 3 hours, the reaction mixture was filtered through a bed of celite, and then concentrated to give 1-{4-[2-(2-aminomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (395 mg) which was purified by recrystallization from a mixture of ethyl acetate and diethyl ether.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1)#[N:3].CN(C=O)C.[CH:29](I)([CH3:31])[CH3:30]>O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH:29]([CH3:31])[CH3:30])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1)#[N:3]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Reactant: CC(C)I
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(C#N)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.8 %

Procedure:
To a mixture of 4′-cyano-2′-nitro-p-toluenesulfonanilide sodium salt (1330 g (3.92 mol)) and DMF (3000 ml), under heating in an oil bath kept at 110° C., isopropyl iodide (2019 g (11.8 mol)) was added over a period of 1.5 hours. After completion of the addition, the mixture was further heated at the same temperature with stirring for 3 hours, and then left to cool to room temperature. Water (1500 ml) was added to bring about separation of crystals. The crystals were filtered, washed with water, dried, and then suspended in diethyl ether. The suspension was stirred for 4 hours, and the insolubles were removed by filtration, the diethyl ether solution was washed with 0.1% aqueous sodium hydroxide solution to remove the remaining starting material, 4′-cyano-2′-nitro-p-toluenesulfonanilide. The diethyl ether layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude crystals which were, after washing with ethanol, recrystallized from ethyl acetate to give 124 g (8.8%) of the title compound as pale yellow crystals.