Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1cccnc1
Yield: 22.4 %

Procedure:
To a solution of toluene (50 mL) cooled to −78° C. was added 2.5 M butyllithium in hexanes (6.31 mL, 15.1 mmol) and the reaction mixture was stirred until the temperature returned to −78° C. 3-Bromopyridine (1.88 g, 11.9 mmol) in toluene (5 mL) was added to the reaction mixture a rate such that the temperature never went above −65° C., and then the reaction was stirred at −78° C. for 1 hour. (S,E)-N-(2-(tert-Butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 10.8 mmol) in toluene (1 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −70° C., and then the reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine and the mixture partitioned between ETOAc/water. The organic layer was washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (15-80% EtOAc in DCM) to provide (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.862 g, 22% yield) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]([O:28][C:29]([N:31]([CH2:52][CH3:53])[C:32]1[C:33]([CH2:47][O:48][C:49](=[O:51])[CH3:50])=[N:34][CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]([CH2:52][CH3:53])[C:32]1[C:33]([CH2:47][O:48][C:49](=[O:51])[CH3:50])=[N:34][CH:35]=[C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:37]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1COC(C)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCN(C(=O)OC(C)(C)C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.109 mmol) and acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (stage 155.1.2) to give the title compound as an off-white solid. (HPLC: tR 2.88 min (Method A); M+H=586 MS-ES)
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]3)[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]3)[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2nc(Cn3ccc([N+](=O)[O-])n3)cs2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2nc(Cn3ccc(N)n3)cs2)OCCO1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1M solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-4-(3-nitro-pyrazol-1-ylmethyl)-thiazole (160 mg, 0.54 mmol), iron powder (91 mg, 1.62 mmol) and NH4Cl (146 mg, 2.70 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an oil. LC-MS-conditions 02: tR=0.60 min; [M+H]+=267.30.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:5][CH2:4]1.CO.C(N(CC)CC)C.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(OCC)C>[Br:1][CH2:2][CH:3]([OH:5])[CH2:4][S:25][C:22]1[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=1
Reactant: BrCC1CO1
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(SCC(O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a stirred solution of 75.3 g [46.7 ml (0.55 mole)] 1-bromo-2,3-epoxypropane (epibromohydrin) in 14 ml 1:1 methanol/triethylamine cooled to 0°-5° C. in an ice-water bath, 83 g (0.5 mole) p-tert-butyl-thiophenol was added dropwise. After the addition was complete, the reaction mixture was allowed to come to room temperature and was stirred at room temperature for about 2 hours. The reaction mixture was dissolved in ethyl ether; washed with 1N sodium hydroxide, with 2N hydrochloric acid, with water until neutral and then with brine (twice). The organic phase was dried, filtered and concentrated to give 140.6 g of the above-identified product as an orange-red oil.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)([CH:1]2[CH2:3][CH2:2]2)[CH3:5])=[CH:8][CH:9]=1
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (3.05 mmol) of the compound from Example 138A and 0.28 ml (3.66 mmol) of trifluoroacetic acid were added to 541 mg (3.05 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified three times by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 441 mg (41% of theory) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Fc1ccccc1CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2F)cc1
Yield: 74 %

Procedure:
Prepared in analogy to example 8 from 4-nitrophenol and 2-fluoro-benzylbromide. Colorless solid. Yield=74%. MS: m/e=247.1 (M+).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:8]1.CI>O1CCCC1>[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=2[CH3:1])=[N:8]1
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc(C2=NC(C)(C)CO2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Reaction time: 2 h

Procedure:
n-Butyllithium (52.8 ml of a 2.5M solution in hexanes) was added dropwise to a stirred solution of the product of step (i) (27.6 g) in tetrahydrofuran (100 ml)at -20° C. After 2 hours methyl iodide (85.3 g) was added and the mixture was stirred for 2 hours at this temperature then 0.5 hours at room temperature. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous solution was extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate inisohexane. Used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@H]3C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a 50-mL round-bottomed flask was added 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((R)-1-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.130 g, 0.168 mmol), 2,2,2-trifluoroacetic acid (5 mL, 0.842 mmol), and trifluoromethanesulfonic acid (0.2 mL, 0.168 mmol).The solution was stirred at 70° C. for 30 minutes. The volatiles were removed under a vacuum and the residue was cooled in ice bath and neutralized with 1 N NaOH. The mixture was stirred at room temperature overnight and the precipitate was filtered and washed with water. The precipitate was purified with preparative TLC using 5% (MeOH in DCM). The sample dried overnight under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((R)-1-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.047 g, 0.088 mmol, 52.5% yield). m/z (ESI, positive ion) 532.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.26 Hz, 3H) 1.38 (d, J=6.65Hz, 3H) 2.45 (m, 4H) −2.55 (m, 1H) 2.84 (s, 5H) 3.01-3.18 (m, 3H) 3.94 (s, 3H) 4.00 (d, J=6.85 Hz, 1H) 7.74-7.78 (m, 1H) 7.88-7.92 (m, 1H) 8.31-8.34 (m, 1H) 8.37-8.43 (m, 2H) 8.70-8.74 (m, 1H) 11.93 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO.O>[CH3:1][N:2]([CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: O=C1CCOCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CN(C1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 30 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.33 mmol, 1.00 equiv) in methanol (10 mL) was added oxan-4-one (66 mg, 0.66 mmol, 2.00 equiv), NaBH3CN (104 mg, 1.65 mmol, 5.0 equiv) and acetic acid (0.1 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h at 30° C. and diluted with water, extracted with EtOAc, washed with brine. The organic layer was concentrated in vacuo. The crude product (130 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 54.0% in 14 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 1-N-methyl-1-N-(oxan-4-yl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (16.2 mg) as a light yellow solid. MS (ES, m/z): 387 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.35 (s, 1H), 4.20-4.33 (m, 1H), 4.05-4.16 (m, 2H), 3.61-3.70 (m, 1H), 3.47-3.56 (m, 3H), 3.17 (t, 2H, J=6.8 Hz), 3.06 (t, 2H, J=6.8 Hz), 2.85 (s, 3H), 2.56-2.65 (m, 2H), 2.27-2.32 (m, 2H), 2.18-2.25 (m, 2H), 2.01-2.16 (m, 2H), 1.91-1.97 (m, 1H), 1.79-1.89 (m, 3H), 1.69-1.75 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:31])=[C:7]([C:18]([NH:21][S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:2][CH2:3][CH3:4].O>CO.C1COCC1.[Pd]>[CH2:1]([C:5]1[C:6]([CH3:31])=[C:7]([C:18]([NH:21][S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:19][CH:20]=1)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)O)c1C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of Example 114A (87 mg) in methanol (4 mL), THF (4 mL), and water (1 mL) was treated with 5% Pd/C (100 mg), stirred under a hydrogen atmosphere for 1 hour, and filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product (47 mg). 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.29-1.34 (m, 2H), 1.40-1.45 (m, 2H), 2.21 (s, 3H), 2.52 (t, 2H), 6.81 (d, 1H), 7.07 (t, 1H), 7.58 (t, 1H), 8.07 (d, 1H), 8.77 (d, 1H), 8.83 (s, 1H); MS (ESI(−)) m/e 347 (M−H)−.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([C:41]1[C:46]([CH:47]=O)=[CH:45][CH:44]=[CH:43][N:42]=1)(=[O:40])=[O:39]>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:47][C:46]2[C:41]([S:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])(=[O:40])=[O:39])=[N:42][CH:43]=[CH:44][CH:45]=2)=[C:20]1[CH3:29]
Reactant: O=Cc1cccnc1S(=O)(=O)c1ccccc1Cl
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2Cl)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A mixture of triethylsilane (0.76 mL), trifluoroacetic acid (0.61 mL) and 1,2-dichloroethane (3.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.070 g), 2-(2-chlorobenzenesulfonyl)-pyridine-3-carbaldehyde (0.089 g) and 1,2-dichloroethane (6.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature for 4 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:4 to 4:1 by volume). Further purification by crystallisation from ethyl acetate and pentane gave the title compound as a white solid (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][N:26]4[C:30](=[O:31])[C:29]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]5[C:27]4=[O:36])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2nsc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.72 g, 0.02 mole), potassium carbonate (4.14 g, 0.03 mole) and N-(2-bromoethyl)phthalimide (6.35 g, 0.025 mole) in 200 ml of acetonitrile is heated at reflux for 4 hours. The solids are then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography over silica gel to provide N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[CH:12]([S:31]([O-:34])(=[O:33])=[O:32])[N:11]([CH3:35])[C:10]1=[O:36].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3Cl)C=C(OC)C=2)CN(C)C1=O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CNC1=O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(C(F)(F)F)C=2)CN([S:125]([O-:128])(=[O:127])=[O:126])C1=O>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:15]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:17]=2)[CH2:12][N:11]([S:125]([O-:128])(=[O:127])=[O:126])[C:10]1=[O:36].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[CH:12]([S:31]([O-:34])(=[O:32])=[O:33])[N:11]([CH3:35])[C:10]1=[O:36]
Reactant: O=C1N(c2c(Cl)cccc2Cl)c2cc(C(F)(F)F)cc(-c3ccc(F)cc3F)c2CN1S(=O)(=O)[O-]
Agent: CN1C(=O)N(c2c(Cl)cccc2Cl)c2cc(C(F)(F)F)cc(-c3ccc(F)cc3Cl)c2C1S(=O)(=O)[O-]
Agent: COc1cc(-c2ccc(F)cc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)N(C)C2
Agent: O=C1NCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=C1N(c2c(Cl)cccc2Cl)c2cc(C(F)(F)F)cc(-c3ccc(F)cc3Cl)c2CN1S(=O)(=O)[O-]

Procedure:
The title compound was prepared from 1-(2,6-dichlorophenyl)-3-methyl-5-(2-chloro-4-fluorophenyl)-7-trifluoromethylsulfonato-3,4-dihydro-2(1H)-quinazolinone as described in EXAMPLE 41. 1-(2,6-dichlorophenyl)-3-methyl-5-(2-chloro-4-fluorophenyl)-7-trifluoromethylsulfonato-3,4-dihydro-2(1H)-quinazolinone was prepared from 1-(2,6-dichlorophenyl)-3-methyl-5-(2-chloro-4-fluorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinazolinone (INTERMEDIATE 58) as described in INTERMEDIATE 48 and INTERMEDIATE 60. 1H NMR(CDCl3, 500 MHz): diastereomeric atropisomers δ 1.32 (m, 3H), 2.37 (brs, 2H), 2.51 (brm, 1H), 3.10 (t, 2H, J=5.7 Hz), 3.53 (brs, 2H), 4.36 (m, 0.5H), 4.47 (m, 0.5H), 5.51 (d, 0.5H, 2.9 Hz), 5.58 (d, 0.5H, J=2.7 Hz), 5.90 (brs, 1H), 6.13 (s, 0.5H), 6.15 (s, 0.5H), 6.83 (s, 0.5H), 6.90 (s, 0.5H), 7.09-7.13 (m, 1H), 7.28-7.42 (m, 3H), 7.51-7.58 (m, 2H). MS(ES) 516 (M+H); LC 1: 2.22 min.
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[Cl:22])[C:12]([CH:14]=[CH:15][C:16](O)=[O:17])=[O:13].ClC(OCC)=O.N>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH:14]=[CH:15][C:16]([NH2:3])=[O:17])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
28 ml of triethylamine was dissoved in 600 ml of cloroform, then 49 g of 3-(3,4-dichlorobenzoyl)acrylic acid was added. The resulting solution was cooled to 0° C, and 42 g of ethyl chloroformate was added. The mixture was warmed to 20° C, stirred for one hour, cooled to 0° C and then held there while gaseous ammonia was passed into the solution until no further heat of reaction was noted. A precipitate that formed was collected, washed with water and then with acetone to give 4-(3,4-dichlorophenyl)-4-oxo-2-butenamide (4A), as a white solid, m.p.: 208° C (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:36][CH2:35][CH2:33][OH:34])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: NCCO
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(NCCO)c([N+](=O)[O-])c4)s3)cc2)CC1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A mixture of [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone (of Example 15; 0.25 g, 0.53 mmol), ethanolamine (0.13 mL, 2.12 mmol), N,N-diisopropylethylamine (Aldrich) (0.37 mL, 2.12 mmol) in n-butanol (10 mL) was heated at 100° C. overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using MeOH/CH2Cl2 (1/9) as the eluent to afford 73 mg (28% yield) of the title compound. Mass spectrum (ES) MH+=498.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH3:18].S(=O)(=O)(O)O.[CH3:24][C:25](=[CH2:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([C:7]1[CH:6]=[C:5]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:4]=[C:3]([CH3:18])[C:2]=1[OH:1])([CH3:26])([CH3:24])[CH3:27]
Reactant: C=C(C)C
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(C)(C)c1cc(C)c(O)c(C(C)(C)C)c1

Procedure:
Into 35.0 parts of methyl 5-(4-hydroxy-3-methylphenyl)-5-methyl-hexanoate from Example 9, 2.0 parts of 98% sulphuric acid, and 200 parts of toluene, was passed isobutylene for 2 hours at 75° C. After washing the toluene solution with 10% sodium hydroxide solution and then water, the toluene was stripped off and the residue distilled to give methyl 5-(3-t-butyl-4-hydroxy-5-methylphenyl)-5-methyl-hexanoate b0.3 168°-72° C. with the following percentage composition by weight.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1N
Reactant: O=Cc1ccccn1
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccccn1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and pyridine-2-carbaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.67 (dt, 1H, J=1.3 Hz, 5.0 Hz), 8.48 (s, 1H), 8.21 (dt, 1H, J=1.1 Hz, 8.4 Hz), 7.79 (td, 1H, J=1.8 Hz, 7.8 Hz), 7.36 (m, 1H, J=1.0 Hz, 5.0 Hz, 7.6 Hz), 7.30 (d, 1H, J=2.2 Hz), 6.91 (d, 1H, J=1.8 Hz), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccc(F)cc23)CC1

Procedure:
(28.1 mg, 53%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.1 mg, 0.131 mmol) and 4-chlorophenylsulfonyl chloride (55.3 mg, 0.26 mmol); HRMS-FAB+ for C20H19N2O2SClF calculated MH+ : 405.08998; found: 405.08291.