Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:32][C:29]1[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:27][C:26]([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:31][N:30]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)nc(C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a flame dry 15 mL round-bottom flask was added 4-(1-(6-fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholine (0.160 g, 0.459 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.122 g, 0.551 mmol), and THF (4.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (1.837 mL, 1.837 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl. The reaction mixture was partitioned between water and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, DCM:EtOAc:MeOH=65%:32%:3%) to afford the product as a yellow solid (175 mg). MS (ESI pos. ion) m/z: 550.0. 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (d, J=6.58 Hz, 3H) 2.34-2.48 (m, 2H) 2.49-2.60 (m, 2H) 2.66 (s, 3H) 2.81 (s, 3H) 3.13 (s, 3H) 3.39 (d, J=6.58 Hz, 1H) 3.72 (t, J=4.38 Hz, 4H) 6.75 (br. s., 1H) 7.45 (s, 1H) 8.01 (d, J=1.90 Hz, 1H) 8.30 (d, J=1.90 Hz, 1H) 8.52 (d, J=2.48 Hz, 1H) 8.76 (d, J=2.48 Hz, 1H) 12.43 (s, 1H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH2:26]3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:46][C:47]([CH3:49])=[O:48]>O1CCCC1.C(O)(=O)C>[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH:26]3[C:47]([OH:48])([CH3:49])[CH3:46])[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Reactant: CC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a stirred solution of 60 μL of hexamethyl disilazane in 10 mL of dry tetrahydrofuran at 0° under argon was added dropwise 190 μL of butyllithium (1.37M in hexane). To this solution at -78° was added a solution of 106 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 1 mL of tetrahydrofuran over a 3 min period. The reaction mixture was stirred for 10 min after which time 25 μL of acetone was added. After 20 min, 50 μL of acetic acid was added, the reaction mixture was evaporated to a small volume, and partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was subjected to preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with ether-petroleum ether (1:2) to afford 21 mg (17.4%) of solid 3 -phenylthio-6-(2-hydroxyprop-2-yl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester. IR (neat): 3400, 1765, 1685, 1545 cm-1 ; NMR (220 MHz; CDCl3): δ 1.17 (3H, s), 1.25 (1H, s), 1.32 (3H, s), 2.30 (1H, J=18, 3.5), 2.8-3.0 (2H, m), 3.11 (1H, dd, J=6, 3), 4.5 (1H, m), 6.93 (1H, s), and 7.2-7.6 (15H, m).
Reaction SMILES: OB1C2C=CC(OC3C=CC(C#N)=C(N4CCOCC4)N=3)=CC=2CO1.[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([B:44]3[O:48][C:47](C)(C)C(C)(C)[O:45]3)=[C:40](C=O)[CH:39]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27].[BH4-].[Na+]>>[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]3[B:44]([OH:45])[O:48][CH2:47][C:42]=3[CH:43]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27]
Reactant: CCOc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 8 h

Procedure:
Experimental procedure for synthesis of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile (D107) is the same as that described in synthesis of (D46). The reaction of 2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (6) (2.71 g, 7.81 mmol) with NaBH4 (886 mg, 23.4 mmol) gave an orange oil containing D107upon workup. The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with 30% MeOH/CH2Cl2 (400 mL) followed by the addition of silica gel (80 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (160 g, 230-400 mesh) and eluted with 1:1:100 acetic acid:MeOH:CH2Cl2. The fractions containing D107were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with methanol (30 mL) followed by the addition of deionised water (400 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D107was obtained (1.82 g, with 30 mol % pinacoldiol present as established by H NMR). To increase purity of D107, it was resubjected to column chromatography and freeze-dried following the same conditions as before to give D107 (402 mg, 17% isolated yield) as a white solid. 1H NMR 400 MHz (d6-DMSO) 89.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.8, 2.0 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); Mass Spectrum [M+H+]=297; HPLC purity 97.18% (Maxplot), 97.65% (220 nm).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>CN1C(=O)CCC1>[C:11]([NH:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CSc1nc(Cl)cc(NC(C)=O)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CSc1nc(NC(C)=O)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 93.8 %

Procedure:
TEA (0.32 ml, 2.28 mmol) and N-[6-chloro-2-(methylthio)pyrimidin-4-yl]acetamide (Intermediate 44, 0.50 g, 2.28 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.46 g, 2.28 mmol) in NMP (2 ml) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 10 minutes. The mixture was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with water two more times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (816 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([S:11][CH3:12])=[N:10][C:3]=12.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[C:9]([S:11][CH3:12])=[N:10][C:3]=12
Reactant: CSc1nc2c(C)ccnc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(SC)nc3c(C)ccnc32)cc1
Reaction time: 0.5 h

Procedure:
200 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]-pyridine and 370 mg of methyl 2-(4-bromomethylphenyl)benzoate was dissolved in dimethylformamide, and 48 mg of sodium hydride was added at room temperature to the solution under stirring. The reaction was allowed to proceed for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=10:1→3:2) to prepare the intended product as a colorless oleaginous substance. The yield was 60 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:38][C:39](Cl)=[O:40])[CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:12][C:10]1[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1N
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1NC(=O)Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a suspension of methyl 2-amino-4-chloro-5-(1-methyl-1H-indol-5-yl)benzoate (Intermediate 45) (150 mg, 0.427 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.131 mL, 0.940 mmol) and [3-(methyloxy)phenyl]acetyl chloride (Acros Organics, 79 mg, 0.427 mmol) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 1 h before being quenched with 1N HCl. The organic layer was separated and washed successively with sat. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by chromatography using a cyclohexane to cyclohexane/EtOAc 80:20 as eluant. The appropriate fractions were combined and concentrated in vacuo to give the title compound methyl 4-chloro-5-(1-methyl-1H-indol-5-yl)-2-({[3-(methyloxy)phenyl]acetyl}amino)benzoate (150 mg, 0.324 mmol, 76% yield) as a white amorphous solid. LCMS: (M+H)+=463; Rt=4.23 min.
Reaction SMILES: [F:1][C:2](=[C:5]([F:7])[F:6])[CH2:3]Br.[P:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C(#N)C>[F:6][C:5]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[C:2]([F:1])=[CH2:3].[F:1][C:2](=[C:5]([F:7])[F:6])[CH2:3][P:8](=[O:9])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: FC(F)=C(F)CBr
Reactant: CCOP(OCC)OCC
Solvent: CC#N
Product: C=C(F)C(F)(F)P(=O)(OCC)OCC
Product: CCOP(=O)(CC(F)=C(F)F)OCC
Yield: 11 %
Yield: 14 %

Procedure:
A solution of 2,3,3-trifluoro-2-propenyl bromide (5.25 g, 30 mmol) and triethyl phosphite (4.15 g, 25 mmol) in acetonitrile (15 mL) was heated at reflux for overnight. The residue obtained after evaporation of the solvent was chromatographed over silica gel (hexanes/ethyl acetate/ethanol, 80/20/1) to give diethyl (1,1,2-trifluoro-2-propenyl)phosphonate (0.8 g, 11%) and diethyl (2,3,3-trifluoro-2-propenyl)phosphonate (1.0 g, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C=CC(NC)=NC=1.[NH2:23][CH2:24][CH2:25][OH:26]>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:11])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: CNc1ncc(Br)cc1S(=O)(=O)Cl
Agent: CNc1ccc(Br)cn1
Product: CNc1ncc(Br)cc1S(=O)(=O)NCCO

Procedure:
Prepared according to the methods described in reagent preparation 25 using 5-bromo-2-(methylamino)pyridine-3-sulfonyl chloride (prepared from 5-bromo-N-methylpyridin-2-amine using analogous conditions to those described in WO2008144463) and 2-aminoethanol in step 1.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27][CH:26]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)=[CH:26][N:27]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2cncc3ccccc23)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 53 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 4-bromo-isoquinoline, the title compound was formed in 53% yield as a white solid, mp 256°-259° C. (dec). free base: 1H NMR (CDCl3, 250 MHz) 9.10 (s, 1H), 8.82 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 7.26 (m, 4H), 6.94 (m, 4H), 4.29 (s, 1H), 3.53 (s, 2H), 2.91 (m, 4H), 2.64 (d, J=1.3 Hz, 2H), 2.28 (m, 4H) MS (CI, CH4) m/z 433 (M+1,100), 461 (M+29,14), 415 (26), 123 (12) hydrochloride salt:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:31]=1[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:32][C:31]3[CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[CH:35]=[CH:36][C:30]=3[F:29])=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3cc(C(F)(F)F)ccc3F)c3c(c21)CC(C)(C)O3
Yield: 34.5 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.065 g, 0.363 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.048 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.52 (s, 2H), 3.60 (s, 3H), 7.29 (s, 1H), 7.53-7.63 (m, 2H), 8.48 (s, 2H), 8.86 (d, J=5.4 Hz, 1H), 10.22 (m, 1H), 10.94 (s, 1H); MS [M]+: 568.08.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]3[N:32]4[CH2:33][CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][C:31]4=[N:30][C:25]=3[CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:45].[Cl-]>C(Cl)(Cl)Cl>[NH2:45][C:26]1[C:25]2[N:30]=[C:31]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][N:32]3[C:24]=2[C:23]2[C:28](=[CH:29][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Reaction time: 0.5 h

Procedure:
mCPBA (0.782 g of 77% purity, 3.49 mmol) was added to a solution of tert-butyl 3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (1.0 g, 2.3 mmol) in chloroform (15 mL), and the reaction was stirred for 30 minutes. Ammonium hydroxide (5 mL), and the reaction was stirred for five minutes before the rapid addition of p-toluenesulfnyl chloride (0.4865 g, 2.55 mmol). The reaction was stirred overnight at ambient temperature. The organic layer was separated and concentrated under reduced pressure. The residue was purified by normal phase prep HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 42-minute gradient from 0:100 to 5:95) to provide 550 mg of tert-butyl 6-amino-3-benzyloxy-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate.
Reaction SMILES: Br[C:2]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12]#[N:13])=[CH:6][C:3]=1[C:4]#[N:5].C[S-:15].[Na+]>>[C:4]([C:3]1[C:2]([SH:15])=[C:9]([CH:8]=[C:7]([C:12]#[N:13])[CH:6]=1)[C:10]#[N:11])#[N:5]
Reactant: C[S-]
Reactant: N#Cc1cc(C#N)c(Br)c(C#N)c1
Agent: [Na+]
Product: N#Cc1cc(C#N)c(S)c(C#N)c1

Procedure:
If the procedure described in Preparation LV is followed starting from 6 g (26.10-3 mol) of 2-bromo-3,5-dicyanobenzonitrile and 6 g (86.10-3 mol) of sodium thiomethylate, 6 g (quantitative yield) of the expected product are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:27]2[N:35]3[C:30]([CH:31]=[N:32][C:33](OS(C(F)(F)F)(=O)=O)=[N:34]3)=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:33]2[N:32]=[CH:31][C:30]3=[CH:29][CH:28]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=4)[N:35]3[N:34]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)c1
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Product: CN1CCCC1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) 69.8 (brs, 1H), 9.7 (s, 1H), 9 (s, 1H), 8.6 (s, 1H), 8.4 (d, J=7.9 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.8 (t, 1H), 7.5 (d, J=8.9 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.7 Hz, 1H), 7 (d, J=4.7 Hz, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.3 (s, 3H), 3.1 (m, 1H), 3.0 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.6 (m, 1H); LC/MS (ESI+): 512 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cccc(CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
A solution of 43.00 g (0.18 mole) of 2-benzyloxy-3-methoxyl-benzaldehyde of Example 1 in 300 mL of absolute ethanol is treated, with stirring, with 7.56 g (0.20 mole) of sodium borohydride. The temperature rises to 50° C. After one-half hour 10 of acetone is added, keeping the temperature at less than 60° C. with cooling. After 15 minutes the volatiles are stripped off at reduced pressure. Ice water (500 mL) is added and the product is extracted into 600 mL of ethyl acetate. The dried (Na2SO4) solution is concentrated. The remaining oil is dissolved in 100 mL of warm ether. Petroleum ether is added to turbidity to give 37.70 g (86% yield) of pure product; mp 58°-60° C.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(C(F)(F)F)=O>[CH2:36]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:28])=[O:29])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.36 mmol) was dissolved in TFA (3 ml) and heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was concentrated and the residue was repeatedly dissolved in DCM and evaporated. The crude product was dissolved in dry MeCN (3 ml) and potassium carbonate (0.251 g, 1.82 mmol) and benzylbromide (0.075 g, 0.44 mmol) was added. The reaction mixture was heated at 120° C. for 15 mins and then at 130° C. for 5 mins in a microwave reactor. The reaction mixture was purified by silica gel column chromatography using a 90:10 mixture of hexane and EtOAc as eluant, to give the title compound (0.088 g, 54%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.49 (m, 4H), 7.48-7.31 (m, 6H), 7.31-7.25 (m, 2H), 7.23-7.17 (m, 1H), 7.11-7.05 (m, 2H), 5.31-5.25 (m, 1H), 4.85 (s, 2H), 2.90-2.82 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.33 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.3, 141.7, 135.6, 134.6, 131.8, 130.0, 129.0, 128.9, 128.9, 128.6, 128.5, 128.5, 126.2, 125.1, 107.0, 44.2, 43.8, 35.4, 29.2, 28.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](O)(=O)[CH3:14]>C(OCC)C>[N+:10]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8][C:14]1[CH:13]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])([O-:12])=[O:11]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1SCl
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To 1.37 g. of 3-butenyltributyltin was added 0.89 g. of 4-chloro-2-nitrobenzene sulfenyl chloride dissolved in 20 ml. glacial acetic acid at steam bath temperature. The mixture was then heated on a steam bath for 30 minutes and poured into an ice water bath. The product was taken up in diethyl ether, washed twice with 50 ml. portions of water, twice with 50 ml. portions of saturated sodium bicarbonate and an additional time with 50 ml. of water. The resulting ether layer was separated, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the concentrate analyzed by proton nmr. The product proved to be cyclopropylcarbinyl 2-nitro-4-chlorophenyl sulfide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]=[CH:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=4)[CH:33]=[N:34][CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CBr)cc1-c1ccccc1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1-c1ccccc1
Temperature: 60 °C

Procedure:
5-Bromomethyl-biphenyl-2-carbonitrile from step 4 (51 mg, 0.19 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (100 mg, 0.19 mmol) were dissolved in CH3CN (950 μl) and heated to 60° C. for 14 hours. The solvent was removed in vacuo and th ressidue dissolved in MeOH (950 μl). The reaction mixture was heated to 60° C. for 4 hours. Solvent was removed in vacuo and the residue was purified by flash chromatography [15% MeOH(5 % NH4OH)/CH2Cl2 ] to yield the final product.