Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1.C1COCC1.[Li]CCCC.[CH2:20]([CH:22]([C:25]1[C:26]2[N:27]([C:32](I)=[C:33]([CH3:35])[N:34]=2)[N:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:23][CH3:24])[CH3:21]>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].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]>[CH2:20]([CH:22]([C:25]1[C:26]2[N:27]([C:32]([C:6]3[S:5][CH:4]=[C:3]([N:2]([CH3:9])[CH3:1])[C:7]=3[CH3:8])=[C:33]([CH3:35])[N:34]=2)[N:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:23][CH3:24])[CH3:21]
Reactant: Cc1cscc1N(C)C
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3scc(N(C)C)c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
To a −78° C. solution of dimethyl-(4-methyl-thiophen-3-yl)-amine (0.43 g, 3.06 mmol) and THF (5 mL) is added 1.6 M n-BuLi (1.91 mL, 3.06 mmol). The solution is stirred for 1 hour, then 0.5 M ZnCl2 (6.1 mL, 3.06 mmol) is added and the solution warmed to ambient temperature. After 30 minutes 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.70 g, 2.04 mmol) and PdCl2(dppf) (0.075 g, 0.10 mmol) is added and the solution heated at 65° C. overnight. The solution is diluted with EtOAc (35 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (15%-30% EtOAc gradient) furnish the title compound (0.13 g, 0.36 mmol, 18%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.03 (s, 3H), 2.45 (s, 3H), 2.50 (s, 3H), 2.77 (s, 6H), 3.28-3.37 (m, 1H), 6.63 (s, 1H), 6.65 (s, 1H). LC/MS (m/z): calcd. for C20H28N4S (M+H)+: 357.2; found: 357.2
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Br.[Br:13][C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:16]2[CH:15]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2 g, 9.215 mmol) in 100 ml ethanol were added 5-bromo-thiazol-2-ylamine hydrobromide (2.396 g, 9.215 mmol) and ethyl-diisopropyl-amine (1.19 g, 9.215 mmol). The mixture was stirred under reflux for 8 h and evaporated. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 532 mg (20%) of the desired product. MS: M+H+=296.96.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Cl.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[ClH:1].[CH2:10]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCCCO
Agent: Cl
Product: CCCCCCOC(=O)[C@@H](N)CS

Procedure:
L-Cysteine hydrochloride (78.5 g) was added to 150 ml of hexanol saturated with dry HCl gas. The mixture was heated under reflux overnight. The solution was evaporated to about half of the total volume, and then ethyl ether (150 ml) was added. The solution gave crystals when it was cooled. The crystals were filtered and were then recyrstallized from ethyl acetate; yield 45 g; mp 89°-90° C.; IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ9.2-8.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH--), 4.3 (t, 2, --OCH2 --), 3.4 (b, 2, CH2S--), 1.0-3.0 (m, 8), 1.0 (t, 3-, CH3).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.[I:17]I>C1COCC1.CCOC(C)=O>[F:9][C:10]1[C:15]([I:17])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: Fc1cccc(F)n1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(I)c(F)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium diisopropylamide (4.34 mL, 8.69 mmol, 2.0 M solution in heptane/THF/ethylbenzene) in THF (20 mL) at −78° C. under a nitrogen atmosphere was added 2,6-difluoropyridine (0.79 mL, 8.69 mmol). The mixture was stirred at −78° C. for 45 min before iodine (2.21 g, 8.69 mmol) in THF (10 mL) was added via syringe. The reaction was stirred for an additional 30 min at −78° C. The reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium sulfite. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give 2,6-difluoro-3-iodopyridine.
Reaction SMILES: [Na+].O1C=CCCC1C([O-])=O.O1CCCCC1C(O)=O.C(Cl)(=O)C(Cl)=O.C(N1CCNCC1)C1C=CC=CC=1.[CH2:39]([N:46]1[CH2:51][CH2:50][N:49]([C:52]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)=[O:53])[CH2:48][CH2:47]1)C1C=CC=CC=1.O1CCCCC1C(N1CCNCC1)=O.[NH2:74][C:75]1[C:84]2[C:79](=[CH:80][C:81]([O:87][CH3:88])=[C:82]([O:85][CH3:86])[CH:83]=2)[N:78]=C(Cl)[N:76]=1>>[O:55]1[CH2:56][CH2:57][CH2:58][CH2:59][CH:54]1[C:52]([N:49]1[CH2:48][CH2:47][N:46]([C:39]2[N:74]=[C:75]([NH2:76])[C:84]3[C:79](=[CH:80][C:81]([O:87][CH3:88])=[C:82]([O:85][CH3:86])[CH:83]=3)[N:78]=2)[CH2:51][CH2:50]1)=[O:53]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCCO1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(C1CCCCO1)N1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C1CCCCO1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCCO4)CC3)nc(N)c2cc1OC

Procedure:
To prepare the compound of formula III, the 3,4-dihydro-2H-pyran-2 carboxylic acid sodium salt is hydrogenated to the tetrahydro-pyran-2-carboxylic acid. This compound converted to the acid chloride with oxalyl chloride and is then treated with N-benzyl piperazine. The resultant N-benzyl-N'-(tetrahydropyran-2-carbonyl)piperazine is hydrogenated to giveN-(tetrahydro-pyran-2-carbonyl)piperazine. This compound is reacted with the known compound 4-amino-2-chloro-6,7-dimethoxyquinazoline to give the active drug 2-[ 4-(tetrahydro-pyran-2-carbonyl)piperazinyl]-4-amino-6,7-dimethoxyquinazoline.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.Cl.[N:13]1([C@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:13]1([C@H:18]2[CH2:22][CH2:21][N:20]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:8])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCN([C@H]2CCNC2)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-fluorobenzoic acid (3.5 g, 24.98 mmol) in DMF is treated with (S)-1,3′-bipyrrolidine dihydrochloride (10.65 g, 49.96 mmol), triethylamine (12.64 g, 124.90 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (5.75 g, 28.98 mmol) and N-hydroxybenzotriazole (4.05 g, 29.98 mmol), stirred at room temperature for 16 h and concentrated in vacuo. The resultant residue is partioned between CH2Cl2 and H2O. The organic phase is separated, washed sequentially with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The concentrate is absorbed onto silica and purified by flash column chromatography (10% methanol in CH2Cl2) to give the title product, identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=O)c1cccs1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetic acid (8 g, 51.2 mmol), suspended in DCM (80 ml) and cooled to 5° C., is added oxalylchloride (5.3 ml, 61.5 mmol), followed by DMF (0.1 ml). Stirring is continued for 1 hour at 5° C. and 18 hours at room temperature. The reaction mixture is evaporated to dryness, toluene is then added and the mixture is evaporated once more to give the title compound as a dark oil.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12]1[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[S:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12]1[N:13]=[C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[S:15][CH:16]=1
Reactant: CCOC(=O)CCc1nc(-c2cc3ccccc3o2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCc1nc(-c2cc3ccccc3o2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
1N Sodium hydroxide (3 ml) was added dropwise to a methanol solution (3 ml) of ethyl 3-[4-(2-benzofuranyl)thiazol-2-yl]propionate (460 mg) under ice-cooling. The reaction mixture was stirred at room temperature overnight, to which was added 10% aqueous potassium carbonate solution (10 ml), and the mixture was washed with ethyl acetate. The aqueous layer was made acidic (pH 3) by adding 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain the entitled compound (306 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH2:25]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH3:26]>CN(C=O)C.CS(C)=O.CO>[CH2:25]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:34][CH2:35]1)(=[O:29])=[O:28])[CH3:26]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCS(=O)(=O)N1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 110 mg, 0.315 mmol) and 1-(ethylsulfonyl)piperazine (174 mg, 0.957 mmol) in DMF (1.28 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (35-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59.9 mg, 39%). Melting point (176.4-180.4° C.). 1H NMR (DMSO-d6) δ: 10.91 (s, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.20 (s, 1H), 3.69-3.93 (m, 4H), 3.34-3.55 (m, 4H), 3.16 (q, J=7.3 Hz, 2H), 2.39 (s, 3H), 1.45 (s, 6H), 1.26 (t, J=7.3 Hz, 3H); ESI-MS: m/z 487.3 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:33]1[CH:34]=[CH:35][C:36](/[C:41](/[C:49]2[CH:54]=[CH:53][C:52]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:51][CH:50]=2)=[CH:42]/[C@@H:43]2[NH:47][C:46](=[O:48])[CH2:45][CH2:44]2)=[N:37][C:38]=1[O:39][CH3:40]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:55]([C:52]1[CH:53]=[CH:54][C:49](/[C:41](/[C:36]2[CH:35]=[CH:34][C:33]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:38]([O:39][CH3:40])[N:37]=2)=[CH:42]\[C@@H:43]2[NH:47][C:46](=[O:48])[CH2:45][CH2:44]2)=[CH:50][CH:51]=1)([CH3:58])([CH3:57])[CH3:56]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1-c1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Phenylboronic acid (57 mg), tris(dibenzylideneacetone)dipalladium(0) (19 mg), tri(2-furyl)phosphine (32 mg) and cesium carbonate (151 mg) were added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-42 (80 mg) in 1,4-dioxane (1.5 mL)-water (0.5 mL), and the mixture was stirred at an external temperature of 65° C. for three hours. The reaction solution was left to cool, diluted with ethyl acetate and filtered. The filtrate was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-phenylpyridin-2-yl)ethenyl]pyrrolidin-2-one as an orange oil (81 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:21]=[CH2:22])[C@H:9]([NH:17]C(=O)C)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.OCC(O)C.Cl>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:21]=[CH2:22])[C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[NH2:17])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C)=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(O)CO
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4.1 g (12.27 mmol) of N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamide (Example 115, Step D) and pyridine (1.20 mL, 14.72 mmol) in THF (35.0 mL) was added 1.2 mL (13.5 mmol) of oxalyl chloride at 0° C. The resulting light yellow slurry was stirred at 0° C. for 1.5 h. 1,2-dihydroxypropane (1.80 mL, 24.53 mmol) was added in one portion and the reaction was warmed to rt. The mixture was treated with ethanol (16.0 ml) followed by 6 N HCl (16.0 ml). The reaction mixture was heated at 55° C. for 10 min and then cooled down to rt. When LCMS indicated that most SM was consumed, 200 ml of ethyl acetate was added, and the organic layer was washed consecutively with NaHCO3 solution and sat. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The crude mixture was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
A solution of 18 g (61 mmol) of (R/S)-1-benzyl-pyrrolidin-3-yl carboxylic acid, benzyl ester (from Step A) in 100 mL of CH2Cl2 at 0° C. was treated with 21.3 mL (231 mmol) of benzyl chloroformate while maintaining the internal temperature at less than 6° C. The reaction was allowed to warm to rt overnight. After 24 hours at rt, an additional 10 mL (10.8 mmol) of benzyl chloroformate was added. After 24 hours of stirring at rt, the reaction was concentrated. The residue was purified on a 40L Biotage column using 19:1 v/v hexane/acetone as the eluant to afford 8.42 g (39%) of the title compound as a colorless oil: RF: 0.14 (9:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 2.19-2.22 (m, 2H), 3.15 (m, 1H), 3.45-3.75 (m, 4H), 5.13-5.20 (m, 4H), 7.33-7.41 (m, 10H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14](=O)[NH:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.CN.[CH:29]([N:32](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:32][CH3:29])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (585 mg, 1.216 mmol), methylamine (1.82 mL of 2 M in THF, 3.65 mmol) and diisopropylethylamine (0.42 mL, 2.43 mmol) in DMF (1.5 mL) was added 1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (591 mg, 1.33 mmol). The reaction was stirred at RT for 18 h, then diluted with H2O (5 mL) and extracted with EtOAc (2×15 mL). The combined organic solution was washed with brine, dried over MgSO4, and concentrated. The residue was suspended in 5 mL of EtOAc, and filtered to 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (507 mg, 84%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 495.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1H, s), 8.13 (1H, d, J=8.8 Hz), 7.98 (2H, d, J=8.4 Hz), 7.91 (1H, m), 7.71 (1H, m), 7.70 (1H, m), 7.44 (2H, d, J=8.0 Hz), 2.88 (3H, d, J=4.9 Hz), 2.35 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].O.[C:20](Cl)(Cl)=[S:21]>CCOCC>[C:8]1([C:7]2[C:2]([N:1]=[C:20]=[S:21])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ncccc1-c1ccccc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: S=C=Nc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 G. of 2-amino-3-phenylpyridine and 7.4 g. of calcium carbonate in 500 ml. of water is added to a solution of 2.9 ml. thiophosgene in 105 ml. of ether. The reaction mixture is stirred at room temperature for 3 hours and the ether layer is separated. The water layer is extracted with ether and the combined ether extracts dried and evaporated to dryness affording 3-phenyl-2-pyridylisothiocyanate. The residue from the evaporation is allowed to stand at room temperature for 3 days. The reaction mixture is then triturated with ether and filtered affording 9-phenyl-3-(3-phenyl-2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 90°-92° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1.Cl.[C:19]([C:21]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)#[N:20]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:24]2[CH2:25][CH2:26][C:21]([C:19]#[N:20])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23]2)=[S:17])=[CH:11][CH:10]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccccc2)CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added to a suspension of 4-chlorophenyl isothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 mL), and the reaction was then stirred at room temperature for 20 minutes. The mixture was washed with 2N hydrochloric acid, then brine, it was dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a white solid, 3.62 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:34][CH2:33][CH2:32][N:31]=[C:30](OC)[C:29]=2[CH:37]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:9][C:10]1[N:31]2[CH2:32][CH2:33][O:34][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:37][C:29]=3[C:30]2=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)ccc1F
Reactant: COC1=NCCOc2ccc(Cl)cc21
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccc(Cl)cc1-2

Procedure:
By the procedure of Example 5, Step A, the title compound was prepared from tert-butyl[(1R)-1-(2,5-difluorobenzyl)-3-hydrazino-3-oxopropyl]carbamate (Intermediate 2) and 7-chloro-5-methoxy2,3-dihydro-1,4-benzoxazepine (Intermediate 15). LC-MS 491 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].Br[C:22]1[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: Cn1cnc(Br)c1
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cn(C)cn2)CC1C(=O)NCc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Yield: 11.8 %

Procedure:
To a stirred mixture of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (100 mg, 0.33 mmol) (prepared as described in Example 28), 4-bromo-1-methyl-1H-imidazole (63.8 mg, 0.396 mmol) in 1,4-dioxane (6 ml) was added potassium phosphate (350 mg, 1.65 mmol), copper (I) iodide (62.8 mg, 0.33 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.052 ml, 0.33 mmol) and the mixture was heated at reflux under argon for 1 h. The mixture was cooled to room temperature and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-20% methanol in dichloromethane, followed by mass-directed automated HPLC to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxamide (15 mg, 12%). LC/MS [M+H]+=384, retention time=1.71 minutes.