Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C.CCOC(C)=O>[C:22]([O:21][C:20]([N:19]([C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:9]3[CH:27]=[C:28]([CH2:30][O:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:29]=[C:8]3[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:12][CH:11]=2)=[CH:18][N:17]=1)[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:26])([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 48a (200.0 mg, 0.450 mmol) was treated with 60% sodium hydride (19.2 mg, 0.48 mmol) in DMF (5 mL) for 15 min. tert-Butyl bromoacetate (25.6 mg, 0.25 mmol) was then added, and the resulting mixture was stirred for 5 h at rt. The reaction was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give tert-butyl 2-((tert-butoxycarbonyl)(5-(8-morpholino-2-((quinolin-2-yloxy)methyl)imidazo[1,2-a]pyrazin-5-yl)pyridin-2-yl)amino)acetate as an off-white solid, which was subsequently deprotected with TFA following the methods described in the Example 47, Step B to afford the title compound 107 as an off-white solid after trituration with ether. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.84-3.93 (m, 4H), 4.27 (s, 2H), 4.31-4.39 (m, 4H), 5.66 (s, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.31 (s, 1H), 7.39-7.45 (m, 1H), 7.66 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.95-8.01 (m, 2H), 8.12-8.18 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H25N7O4: 512.2 [M+H]. found 512.2.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1.ClCCl>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[C:32]([CH:34]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35]2)[CH:33]=1
Reactant: C=C(N=Cc1cc(Br)ccc1OC1CCOCC1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OC2CCOCC2)N1
Yield: 49.3 %

Procedure:
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (1.0 g, 2.5 mmol) was reacted with 1-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (4 g, 10 mmol) in toluene at 140° C., then treated with trifuloroacetic acid in dicloromethane to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.76 g, 49%)
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(OC)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
Boronic acid 4 (329 mg, 1.00 mmol) is coupled to 4-bromoanisole (125 μL, 1.00 mmol) using Method B to give the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=N)[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH2:23]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:23])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=N
Reactant: O
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 20 °C

Procedure:
A suspension of 10 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-imino-imidazoline-2-one, 35 ml of 22° Be aqueous hydrochloric acid and 35 ml of water was refluxed for an hour, cooled to 20° C and poured into water. The mixture was vacuum filtered and the recovered precipitate was washed and dried to obtain 9.5 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione melting at 149° C. A microanalytical sample after crystallization from ethanol melted at 149° C.
Reaction SMILES: [C:1]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[C@H:2]([CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[OH:3].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:18]([C@H:4]([C@H:2]([OH:3])[C:1]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:17]=[CH2:16]
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a cold (−78° C.) solution of diisopropyl (S)-(−)-malate (4.74 mL; 22.9 mmol; 1.0 eq.) in anhydrous THF (8.50 mL) was slowly added under argon lithium bis(trimethylsilyl)amide (48.1 mL; 1.0 M in THF; 48.11 mmol; 2.1 eq.) keeping the temperature below −66° C. After 45 min of addition, the reaction mixture was stirred at −78° C. for 2 h, then the temperature of the reaction mixture was allowed to reach 11° C. After 1 h at that temperature, the mixture was cooled at −78° C. and allyl bromide (2.9 mL; 34.4 mmol; 1.5 eq.) was added. The solution was stirred overnight allowing the temperature to reach RT. The reaction was then quenched with ice water and an aqueous saturated solution of NH4Cl. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with a saturated solution of NaCl, dried over MgSO4 and evaporated to obtain an orange oil (5.4 g). Purification by chromatography (SiO2, 10/90 EtOAc/c-hex) gave the title product as a colorless oil (3.05 g, 51.5%). 1H NMR (CDCl3, 300 MHz) δ 5.76-5.59 (m, 1H), 5.07-4.80 (m, 4H), 4.08 (d, J=2.3 Hz, 1H), 3.03 (br s, 1H), 2.80-2.72 (m, 1H), 2.53-2.41 (m, 1H), 2.34-2.21 (m, 1H), 1.14 (d, J=6.4 Hz, 6H), 1.07 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:11])[CH:3]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1>[Cl:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: Clc1cc(Br)cc(C2CC2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(C2CC2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 1-bromo-3-chloro-5-cyclopropylbenzene (300 mg, 1.30 mmol) at −78° C. in THF (5 ml) was added nBuLi (890 μl, 1.6M solution in hexane, 1.43 mmol) dropwise. The resulting solution was stirred at −78° C. for 10 min after which solid carbon dioxide was added and the reaction mixture was warmed to RT over 3 hours. The reaction mixture was quenched with water and then extracted with ether. The aqueous phase was then made acidic with 1N HCl and then extracted with ethyl acetate. The organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product 3-chloro-5-cyclopropylbenzoic acid (178 mg, 70%) which did not require further purification. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][C:25]([NH:27][NH2:28])=[O:26].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:28][NH:27][C:25](=[O:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: CC(=O)NN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: O
Solvent: CO
Product: CC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 109 mg, 0.29 mmol) was dissolved in MeOH (5 mL) to which was added acethydrazine (85 mg, 1.1 mmol). The resulting solution was heated on a 45 C oil bath for 16 h, then cooled to room temperature and poured into 15 mL of water. The resulting suspension was cooled to 4 C, then filtered and the solids rinsed with cold water (25 mL). The solids were dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white crystalline solid, which was recrystallized from acetone/MeOH to yield 70 mg (56%) of 4.32 as a white microcrystalline solid which is an inseparable mixture of isomers in a ratio of 60:40: mp 270-271 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): (major isomer) δ 11.25 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70 (s, 2H), 2.24 (s, 3H); (minor isomer) δ 11.41 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70 (s, 2H), 1.95 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): (major isomer) δ 171.39, 135.98, 133.15, 129.73, 126.01, 124.96, 123.86, 121.69, 115.41, 108.31, 88.78, 86.09, 71.41, 69.66, 61.10, 20.36; (minor isomer) δ 165.24, 138.70, 133.12, 129.82, 126.06, 124.96, 123.99, 122.17, 115.33, 108.51, 88.78, 86.09, 71.41, 69.66, 61.10, 21.67. HRMS (ES) m/z calcd. for C16H16Cl3N3O5.Na 458.0053, found 458.0043. Anal calcd for C16H16Cl3N3O5: C, 44.01; H, 3.69; N, 9.62. Found: C, 43.76; H, 3.75; N, 9.67.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.C(OC(=O)[C:31]1[CH:36]=[CH:35]C(I)=[CH:33][CH:32]=1)C>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:4][C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[C:3]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate (Reagent A, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 85.0 mg (91%) of the title compound as an orange oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[NH2:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1>ClCCl>[C:10]([NH:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(C)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
At RT, 12 μl (68 μmol) of N,N-diisopropylethylamine and then 6 μl (62 μmol) of acetic anhydride were added to a solution of 38 mg (62 μmol) of the compound of Example 53A in 0.96 ml of dichloromethane, and the mixture was stirred for 1 h. The volatile components were then removed on a rotary evaporator. Since LC/MS analysis of the crude product indicated additional formation of an O-acetylated byproduct, the residue was dissolved in 2 ml of methanol and 800 μl of 2 N aqueous sodium hydroxide solution were added. After 72 h, the mixture was acidified with 1 N hydrochloric acid and separated by preparative HPLC [Method 8]. In this step, the two product diastereomers were obtained in separated form. This gave 6 mg (16% of theory) of the title compound (Diastereomer 1) and 7 mg (19% of theory) of the second diastereomer (see Example 39).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li][CH2:17]CCC.COS(OC)(=O)=O.Cl>CCOCC>[CH3:17][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: [Li]CCCC
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: Cc1cc2ccccc2c2ccccc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
9-Bromophenanthrene (27 g, 102 mmol) was dissolved in 400 mL of dry ether and cooled to −78° C. 170 mL of BuLi (1.6 M in hexane) was slowly added into this solution in 45 minutes. The reaction mixture was warmed to room temperature. The mixture was then stirred at room temperature for 2 h before it was cooled to −78° C. again and Me2SO4 (17.6 g, 133 mmol) in ether was slowly added. The mixture was stirred at room temperature for 10 h. The mixture was poured into 15% HCl aqueous solution and extracted with CH2Cl2 and dried over MgSO4. The solvent was evaporated to give a residue which was recrystallized from hexane to yield 14.2 g of product as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)(C(C)(C)C)(C)C.[C:19]1([C:25]2[CH:26]=[C:27]([C:34](Cl)=O)[S:28][C:29]=2[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:19]1([C:25]2[CH:26]=[C:27]([C:34]3[O:18][N:17]=[C:15]([C:12]4[CH:11]=[C:10]([CH2:9][OH:8])[S:14][CH:13]=4)[N:16]=3)[S:28][C:29]=2[C:30]([F:33])([F:31])[F:32])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)cs1
Reactant: O=C(Cl)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cs1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1e) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-3-carboximidamide (0.43 g, 1.5 mmol) that was obtained in Example 3 (3b), 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N,N-diisopropylethylamine (0.52 ml, 3.0 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (3.0 ml, 3.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2 to 1:1) as the eluent to afford the title compound (0.60 g) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.O=P(Cl)(Cl)[Cl:28]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:28])=[N:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(Cl)c2ccc(Br)cc2n1
Reaction time: 0.33 h

Procedure:
A solution of 7-bromo-2-methoxyquinazolin-4(3H)-one (1.900 g, 7.45 mmol) in 30 mL DCM was treated with DBU (1.123 ml, 7.45 mmol) and was allowed to stir for 20 minutes. The cloudy purple solution was then treated with POCl3 (0.833 ml, 8.94 mmol) and was allowed to stir for one hour at room temperature. LC/MS showed mostly product, so the reaction mixture was concentrated. The crude residue was carried on to step 3 without purification. (M+H)+=271.2.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[N:10]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCI
Solvent: c1ccccc1
Product: COC(=O)CCCCN1CCCCC1

Procedure:
30.0 g. (0.124 mole) of methyl δ-iodovalerate and 42.5 g. (0.50 mole) of piperidine were dissolved in 250 ml. of benzene and heated at 60° C for 3 hours with stirring. A colorless solid began to appear shortly after the materials were combined. The solid was removed by suction filtration, and the benzene evaporated to give methyl δ-piperidinovalerate which distilled as 23.5 g. (95%) of colorless liquid, b.p. 122°-24° C (12.5 mm.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]([CH3:25])([CH2:19][CH2:20][C:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O>[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[C:12]2[C:17]([CH3:25])([CH3:18])[CH2:19][CH2:20][C:21]([CH3:23])([CH3:22])[C:13]=2[CH:14]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of aluminium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])(O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>[Zn].C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN(C)C(=O)CC1C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A flask is charged with 2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 19) (10.0 g, 30.8 mmol), acetic acid (250 mL), acetic anhydride (100 g), and Zn-dust (20 g). The mixture is kept under reflux, until all of the starting material is consumed (3 h). The solids are then filtered off, and from the filtrate the solvent is removed to leave an oil which crystallizes to a pale brown solid on treatment with di-iso-propyl ether. Yield of the title compound: 9.2 g (96.8%). 1H-NMR (CDCl3, 300 MHz) δ 2.73 (dd, 1, 2J=16.5 Hz, J=9.4 Hz, CH2NMe2); 3.00, 3.01 (2 s, 6, N(CH3)2); 3.20 (dd, 1, J=3.2 Hz, CH2NMe2); 4.06 (dd, 1, H-3); 4.90, 4.97 (AB, 2, 2J=15.6 Hz, CH2N); 6.70 (d, 1, J=7.9 Hz, H-7); 6.97 (“dtr”, J=7.5 Hz, J=1.2 Hz, H-5); 7.13 (“dtr”, J=7.8 Hz, J=1.2 Hz, H-6); 7.22-7.29, 7.29-7.33 (m, 5, 5 Ph-H); 7.38 (br d, 1, J=7.5 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.25 (CH2NMe2); 36.07, 37.51 (N(CH3)2); 42.59 (C-3); 44.28 (NCH2Ph); 109.12 (C-7); 122.66 (C-5); 124.85 (C-4); 127.49 (Ph meta-C); 127.71 (Ph para-C); 128.04 (C-6); 128.92 (Ph ortho-C); 129.63 (C-9); 136.19 (Ph ipso-C); 143.52 (C-8); 170.00 (CONMe2); 178.02 (C-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:13]3([CH2:15][CH:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=S)[NH:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[C:28]([NH:31][NH2:32])(=O)[CH3:29]>CCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:13]3([CH2:15][CH:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]3=[N:32][N:31]=[C:28]([CH3:29])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1NC2=S
Reactant: CC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1-n1c(C)nnc12
Yield: 41.7 %

Procedure:
A solution of ethyl 1-(4-chlorophenyl)-2-oxo-4-thioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (70 mg, 0.17 mmol) and acetohydrazide (60 mg, 0.78 mmol) in n-BuOH (20 mL) was heated at 130° C. overnight. The solution was evaporated and purified by CombiFlash (DCM:MeOH=10:1) to afford ethyl 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylate (30 mg, 41%). LRMS (M+H)+: 422 m/z. 1H NMR (300 MHz, CD3OD): δ 1.04-1.08 (t, J=7.2 Hz, 3H), 1.92-1.97 (m, 1H), 2.10-2.18 (m, 2H), 2.74 (s, 3H), 3.87-4.03 (m, 2H), 6.96-6.99 (m, 1H), 7.23-7.27 (m, 2H), 7.41-7.54 (m, 4H), 7.69-7.72 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[C:32]([CH3:34])([CH3:33])[O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].O.Cl>CCO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[C:32]([CH3:34])([OH:31])[CH3:33])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Yield: 92.9 %

Procedure:
To a mixture of (S)—N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.134 g, 0.255 mmol) in EtOH (5 ml) and water (0.227 ml, 0.255 mmol) was added concentrated HCl (0.0531 ml, 0.637 mmol) and the reaction heated at reflux for 5 hours. The reaction was concentrated to a residue that was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The combined organic layers were dried over Na2SO4, filtered and concentrated to give (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol (0.115 g, 92.9% yield) as a white solid. Mass Spectrum (apci) m/z=468.1 (M+H−H2O).