Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([NH:18][C:8]4[CH:9]=[CH:10][C:11]([N:12]5[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]5)=[C:6]([O:5][CH3:4])[CH:7]=4)[S:20][C:21]=3[CH2:22]2)=[O:34])=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)c2ccc(F)cc2)CC3)ccc1-n1cnc(C)c1

Procedure:
90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 33 mg (0.2 mmol) 4-fluorobenzoyl chloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The reaction was purified on silica gel with methylene chloride/methanol 19/1 yielding 52 mg (56%) (4-fluoro-phenyl)-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-methanone as a yellow solid. MS ISP (m/e): 464.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm) 10.34 (s, 1H), 7.57-7.49 (m, 3H), 7.34-7.24 (m, 4H), 7.02 (d, 1H), 4.70-4.45 (br m, 2H), 4.00-3.55 (br m, 2H), 3.78 (s, 3H), 2.73 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>CCCCCCC.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 2 h

Procedure:
To a vigorously stirred solution of 2-tert-butylphenol (10 g, 66.6 mmol) in heptane (67 ml) was added at a fast drip a solution of 70% nitric acid (4.25 ml, 66.6 mmol) diluted with water (4.25 ml). The resulting dark red/brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration washed with hexane (300 mL), water (200 mL) and once again with hexane (200 mL) to give a cocoa colored powder that was dried to constant mass (4.65 g, 35.6%).
Reaction SMILES: [CH:1]([N:3]([CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>C1(C)C=CC=CC=1>[CH3:18][C:16]1([CH3:19])[CH2:17][CH:12]([N:3]([CH:1]=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][C:14]([CH3:20])([CH3:21])[N:15]1[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCCCCCCCN(C=O)C1CC(C)(C)NC(C)(C)C1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCCCCCCCN(C=O)C1CC(C)(C)N(C=CC(=O)OCC)C(C)(C)C1
Yield: 101.5 %

Procedure:
59.2 g of 4-(N-formyl-N-octylamino)-2,2,6,6-tetramethylpiperidine and 20 g of ethyl propiolate were refluxed in 500 ml of toluene for 20 hours. Removal of the solvent by distillation under reduced pressure resulted in 80 g of the compound of the formula shown below in the form of a dark oil which crystallized after a few days to give a solid at melting point 58°-60° C. ##STR20##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11]2=[O:36])[CH2:3][CH2:2]1.[F:37][C:38]([F:52])([F:51])[C:39]1[CH:40]=[C:41]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[CH:43][CH:44]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:48]4[CH2:47][CH2:46][N:45]([C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:51])([F:52])[F:37])[CH:40]=5)[CH2:50][CH2:49]4)=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11]2=[O:36])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(C3CCC(=O)N3CCCN3CCOCC3)cc2)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C1CCC(c2ccc(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)N1CCCN1CCOCC1

Procedure:
N-(3-morpholinopropyl)-5-[4-(4-(p-toluenesulfonyloxy)butyl)phenyl]pyrrolidin-2-one and 1-(3-trifluoromethylphenyl)piperazine are reacted together to give N-(3-morpholinopropyl)-5-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Li+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CCCn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A solution of 4 g (11.4 mmol) of ethyl 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-butanoate in 40 mL of THF was treated with 40 mL (80 mmol) of lithium hydroxide (2M in water), and the reaction was stirred at rt overnight. The mixture was washed with ether to remove non-acidic impurity. The aqueous layer was acidified with 3 N hydrochloric acid (HCl), and the solid was collected by filtration and dried in vacuo to give 2.77 g (75%) of 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-butanoic acid as an off-white solid: mp 177.0-179.8° C.; 1H NMR (DMSO, d6) δ 1.90 (quintet, J=7.3 Hz, 2H), 2.19 (t, J=6.9 Hz, 2H), 4.30 (t, J=7.7 Hz, 2H), 6.14 (s, 2H), 7.10 (d, J=8.1 Hz, 1H), 7.20-7.34 (m, 4H), 7.65 (dd, J=7.9, 1.2 Hz, 2H), 12.15 (br s, 1H); HRMS (EI) Calc'd for M+ : 325.1188, found: 325.1188. Anal. Calc'd for [C18H16N2O4 +0.43 CH2Cl2 ]: C, 61.39; H, 4.71; N, 7.77. Found: C, 61.39; H, 4.55; N, 7.79.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:22]1([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.Cl>[C:22]1([S:28]([NH:31][N:32]=[C:12]2[CH2:11][CH2:10][C@H:9]3[C@@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C:18]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6][CH2:7]4)(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NNS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)C(=NNS(=O)(=O)c3ccccc3)CC[C@@H]12
Yield: 92.3 %

Procedure:
A suspension of 5.68 g (20 mmol) of 3-methoxy-8α-estra-1,3,5(10)-trien-17-one and 4.30 g (25 mmol) of benzenesulfonic acid hydrazide in 70 ml of ethanol is mixed with 3 drops of concentrated hydrochloric acid and then allowed to react at a bath temperature of 80–90° C. for three hours while being stirred vigorously. After the reaction solution is cooled, the precipitated product is suctioned off, rewashed with a little cold ethanol, and the hydrazone is dried in a vacuum. 8.10 g (92%) of product, which melts at 183–185° C., is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[N:26]1([C:24]([CH:7]([NH:6][C:4](=[O:5])[CH2:3][NH:2][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)NCC(=O)NC(CNC(=O)C2CCN(c3ccncc3)CC2)C(=O)N2CCCCC2)cc1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with 4-toluenesulphonyl chloride to give N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(4-toluenesulphonamido)aceta mide in 50% yield as a foam;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH3:21])([CH3:20])[C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:10]>O1CCCC1>[C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH:9]([C:8]([CH3:21])([CH3:20])[CH3:7])[OH:10])=[CH:12][CH:13]=1)([OH:17])=[O:16]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
To a mixture of 1.95 grams (0.051 mole) of lithium aluminum hydride and 30 ml. of tetrahydrofuran is added a solution of 10.5 grams (0.051 mole) of 4-(2,2dimethyl-1-oxopropyl)-benzoic acid in 110 ml. of tetrahydrofuran. The mixture is stirred for 2 hours at 0°-5° C., and then quenched by the addition of sodium sulfate solution. The resulting mixture is made acidic by the cautious add ition of concentrated hydrochloric acid. The mixture is extracted with ether; and the extracts are then washed with 50% brine, dried over magnesium sulfate, filtered and evaporated. The resulting solid is dissolved in aqueous sodium hydroxide, filtered and after acidification with hydrochloric acid, again extracted with ether, dried over magnesium sulfate, filtered and evaporated to yield the title product (m.p. 161.5°-163° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([F:21])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)=[C:4]([F:21])[CH:3]=1
Reactant: CCOC(=O)N1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=C(c2cc(F)c(Br)cc2F)CC1

Procedure:
A solution of 11.12 g (30.5 mmol) 4-(4-bromo-2,5-difluorophenyl)-1-ethoxycarbonyl-4-piperidinol and 0.70 g of p-toluenesulfonic acid in 200 ml toluene was refluxed with a Dean-Stark trap for 16 hours. The mixture was cooled, extracted with sodium bicarbonate solution, dried (MgSO4), evaporated and the residue flash chromatographed on a column of silica gel to afford a syrup which crystallized on standing, mp 40°-44° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19](=[O:20])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:29][CH2:28]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 71 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-(N—BOC-amino)-piperidine using standard reductive amination conditions. The resulting crude oil was triturated with diethyl ether and methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a solid (71% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 340 as an off white solid (18% yield). NMR (CDCl3, 400 MHz), 1.43-1.48 (2H, m), 1.84 (2H, d, J=10.3), 2.19 (2H, t, J=11.3), 2.70-2.73 (1H, m), 2.93-2.96 (2H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=427
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.CS(C)=O.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>O>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)nc1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a solution of 4-[2-(pteridin-4-ylamino)ethyl]phenol (270 mg, 1.0 mmol) and dry DMSO (5 mL) was added 2-chloro-5-trifluoromethylpyridine (155 mg, 0.85 mmol) and K2CO3 (280 mg, 2.0 mmol). This mixture was heated to 80° C. for 3 h, cooled to ambient temperature, poured into H2O (20 mL) and extracted with CH2Cl2 (20 mL). The CH2Cl2 solution was washed with H2O (2×10 mL), dried with Na2SO4, and the solution was filtered. The solution was concentrated in vacuo, redissolved in a minimum volume of CH2Cl2 and treated with hexane to precipitate a solid. The solid was collected by filtration and dried under vacuum to afford pteridin-4-yl-{2-[4-(5-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine (310 mg) as an off-white solid: mp 147-150° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=1.9 Hz, 1H), 8.85 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.22 (dd, J=5.2, 0.8 Hz, 1H), 7.19-7.05 (m, 3H), 4.01 (dd, J=13.3, 7.0 Hz, 2H), 3.10 (t, J=7.1 Hz, 2H); ESIMS m/z 413 ([M+H]+).
Reaction SMILES: CC([N:5]([C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:31][C:9]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])([CH3:30])[NH2:5]
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
1,1-dimethylethyl[1,1-dimethyl-2-({4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-2-oxoethyl]carbamate (Intermediate 24, 34 mg) was dissolved in 4.0 ml of dichloromethane and then TFA (1.0 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. After removal of the volatiles, the residue was charged on a SCX cartridge and eluted successively with dichloromethane, MeOH, NH3 (2.0 M solution in MeOH). Evaporation afforded 18 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>>[SH:24][CH2:23][CH2:22][CH2:21][S:25][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: SCCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,3-propanedithiol to provide 5-[2-[(3-mercaptopropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.65 and 1.68 (singlets, 3H), 2.41 (m, 2H), 1.73-2.20 (overlapping multiplets, 3H), 2.45-2.65 (m, ˜4H) 3.08-3.27 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.27-7.45 (m, 6H); MS (HR-FAB) m/z 391.0850 (M+H calcd. for C20H23O2S3 391.0860).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:28](Cl)(=[O:31])[O:29][CH3:30]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[O:14])[C:28](=[O:31])[O:29][CH3:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCCC(=O)c1ccccc1F)c1ccc(Br)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)N(CCC(=O)c1ccccc1F)[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(2-fluorophenyl)propan-1-one (500 mg, 1.43 mmol) in anhydrous CH3CN (15 mL) was added K2CO3 and methyl carbonochloridate (403 mg, 4.29 mmol), and the mixture was stirred at rt for 2 h. The solution was concentrate, and the residue was purified by preparative TLC to afford (S)-methyl 1-(4-bromophenyl)ethyl(3-(2-fluorophenyl)-3-oxopropyl)carbamate (400 mg, 70%). 1H NMR (CDCl3): δ=1.50 (m, 3H), 3.00 (m, 2H), 3.36 (m, 2H), 3.78 (m, 3H), 5.40 (m, 1H), 7.11 (m, 4H), 7.28-7.50 (m, 3H), 7.71 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]2[CH2:9][C:4]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)([CH2:5]2)[C:3]1=[O:19].C(OCC)(=O)C>COCCO.[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:4]23[CH2:5][CH:6]([CH2:9]2)[C:7](=[O:8])[N:2]([CH3:1])[C:3]3=[O:19])=[CH:15][CH:14]=1
Reactant: CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: COCCO
Solvent: CCOC(C)=O
Product: CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 197°-198° (from ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 56.5 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.8 mg, 0.12 mmol) in dichloromethane (1 mL) was added propanoyl chloride (11.5 mg, 0.12 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 42.4 mg (56%) of the title compound as off white solid. MS (ES) m/e 625.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10](=[O:15])(=[O:14])[CH2:9][CH2:8][C:7]12OCC[O:16]1)([OH:3])=[O:2].Cl>CC(C)=O.O>[C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10](=[O:15])(=[O:14])[CH2:9][CH2:8][C:7]2=[O:16])([OH:3])=[O:2]
Reactant: Cc1c(C(=O)O)ccc2c1C1(CCS2(=O)=O)OCCO1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(C(=O)O)ccc2c1C(=O)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
16.0 Grams (54 mmol) of 6-carboxy-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide was dissolved in 90 ml of acetone and 30 ml of water, and 10 ml of a 12N hydrochloric acid aqueous solution was added. The mixture was stirred at room temperature for 2 days. After the completion of the reaction, the reaction mixture was concentrated, and extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 13.7 g (yield: quantitative) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][C:7]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2ccc(O)c(I)c2)c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
4′-Hydroxybiphenyl-3-carbonitrile (Preparation 121, 570 mg, 2.92 mmol) was dissolved in dichloromethane (10 mL) and acetic acid (10 mL). Then concentrated sulfuric acid (0.30 mL) and N-iodosuccinimide (657 mg, 2.92 mmol) were added at 0° C. (ice-bath cooling) and the reaction was allowed to warm to room temperature over 2 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in heptane to give the title compound (720 mg, 77%).