Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].N1[CH:33]=[CH:32]C=CC=1.[CH:34]([O-])([O-])[O:35]CC>Cl(O)(=O)(=O)=O>[C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15]([O:17][CH2:32][CH3:33])=[CH:16][CH:34]=[O:35])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC([O-])[O-]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C1
Reactant: c1ccncc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=CC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A stirred solution of 3α-acetoxy-5α-pregnane-11,20-dione (0.375 g.) in ethyl orthoformate (10 ml) at 0° was treated with 9 drops of 75% perchloric acid over 20 minutes. Ca 10 drops of pyridine were then added and the mixture was extracted with ice-cold ether. The organic layer was washed with N hydrochloric acid solution, then aqueous sodium hydrogen carbonate and finally water. It was dried (MgSO4) and evaporated. The residue (0.5 g) was purified by preparative t.l.c. (ethyl acetate/petrol, 1:3) and then crystallisation from methyl acetate/petrol to give the title compound (0.2 g), m.p. 150°-154°, [α]D - 59.8°, λmax. 258.9 nm (ε 15,900).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:6]1(=[O:23])=[O:22].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)C>[F:21][C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]3)[S:6]2(=[O:23])=[O:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Reaction time: 48 h
Yield: 66.9 %

Procedure:
A solution of 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2, 0.5 mmol) in anhydrous dimethylformamide (3 mL) was treated with tert-butyl piperazine-1-carboxylate (0.19 g, 1 mmol) and N,N-diisopropylethylamine (0.17 mL, 1 mmol). The reaction mixture stirred at ambient for 48 h. The reaction mixture was diluted with ethyl ether (10 mL) and washed with H2O (2×10 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/hexane) to provided tert-butyl 4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperazine-1-carboxylate (0.17 g, 67%) as a white solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1S(NC1C=C(C=CC=1)C(O)=O)(=O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Product: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 50 %

Procedure:
Intermediate 5c (solid) is prepared using intermediate 4b and ethyl 4-aminobenzoate using the procedure described for 5a.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].C1(C)C=CC=CC=1>C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 99.2 %

Procedure:
Suspended in 20 ml of ethyl acetate were 10.0 g (65.8 mmol) of trimethylhydroquinone (TMH) and 0.32 g (0.658 mmol) of scandium trifluoromethanesulfonate, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 20.3 g (68.4 mmol) of isophytol in 20 ml of ethyl acetate was added dropwise over 30 minutes under heating and reflux, TMH and isophytol were reacted for 3 hours. The reaction mixture was cooled, to which 100 ml of toluene were added. The resulting mixture was washed twice with 200-ml portions of water and then concentrated under reduced pressure. The residue was added with 100 ml of toluene and 100 ml of 2-butanone. The organic layer was washed twice with 200-ml portions of a 1N aqueous solution of sodium hydroxide and then with 200 ml of a saturated aqueous solution of sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-diethyl ether system), whereby 28.1 g of the title compound were obtained in the form of a brown oil. (Yield: 99%, GLC purity: 95%)
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].Cl[C:14]1[N:19]=[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=1>>[Cl:32][C:17]1[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:19][C:14]([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[S:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[CH:1]=2)=[N:15][CH:16]=1
Reactant: Nc1ccc2c(c1)CNCCS2
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CNCCS3)ncc1Cl
Yield: 84.9 %

Procedure:
Following the procedure of 2f, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00039 mol) and N-[(1S,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.13 g, 0.00039 mol) were reacted giving N-{(1R,2R)-2-[5-chloro-2-(6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (0.16 g, 85%). MP: 141-3° C.; 1H-NMR (DMSO-d6) 9.30 (s, 1H), 7.93-5 (s, 1H), 7.73-9 (s, 1H), 7.44-6 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 3.91 (s, 1H), 3.84-5 (m, 1H), 3.22-4 (m, 2H), 2.93 (s, 2H), 2.63-4 (m, 2H), 2.00-12 (m, 2H), 1.70 (m, 2H), 1.27-37 (m, 4H); LC/MS (ESI+): 483 (M).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[Si:14]([O:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[C:33]1=O)[CH2:39]2>C1COCC1.CCOCC>[Si:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:25][O:27][CH:28]=[C:33]2[CH:34]3[CH2:40][CH:38]4[CH2:37][CH:36]([CH2:41][CH:32]2[CH2:39]4)[CH2:35]3)[CH:29]=[CH:30][CH:31]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A 500 mL three-neck flask was fitted with a reflux condenser, 125 mL addition funnel, and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. Dry THF (200 mL) was added and the flask cooled in an ice bath. TiCL3 (24 g, 156 mmol) was added rapidly followed by LAH (2.8 g, 75 mmol) in portions with stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (12 mL, 86 mmol) was added to the stirred suspension and refluxed for 1 hour. After this period a solution of methyl 3-tert-butyldimethylsilyloxybenzoate (4.40 g, 16.6 mmol) and 2-adamantanone (3.0 g, 20.4 mmol) in 50 mL of dry THF was added dropwise to the refluxing mixture over 5 hours. Refluxing was continued for an additional 4 hours after which the reaction was cooled to room temperature and diluted with 100 mL of ether. The organic solution was separated and concentrated. Chromatography over silica with 1% ethyl acetate/hexane gave 1.29 g (21%) of 7b as an oil: 1H NMR (CDCl3) delta 0.196 (s, 6H), 0.985 (s, 9H), 1.78-1.97 (m, 12H), 2.628 (s, 1H, 3.23 (s, 1H), 3.29 (s, 3H), 6.75-7.20 (m, 4H); 13C NMR (CDCl3) delta -4.50, 18.19, 25.67, 28.37, 30.16, 32.28, 37.25, 38.19, 39.01, 57.51, 119.29, 121.08, 122.32, 128.87, 131.11, 136.84, 143.47, 155.37. ##STR45## Preparation of 1,2-Dioxetanes
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH:18]([O:21][C:22]2[N:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(-c3ccc(C#N)cc3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnc(OC3CCNCC3)nc2)cc1
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution (2.0 ml) of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(4-cyanophenyl)pyrimidine (122 mg, 0.32 mmol) at room temperature, and stirred for 2.5 hours at the temperature. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the entitled compound (90 mg, 100%).
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:21])(=O)=O)=CC=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([CH:44]=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([CH:44]([C:7]2[S:6][C:10]([F:21])=[CH:9][CH:8]=2)[OH:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(F)s2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A 1.6 M solution of n-BuLi in Hex (3.71 ml, 5.9 mmol) was added to a cooled (−78° C.) solution of thiophene (500 mg, 5.9 mmol) in THF (15 ml) under Ar. After stirring 30 min at −78° C. a solution of N-fluorodibenzenesulfonimide (1.87 g, 5.9 mmol) in THF (10 ml) was added. Stirring at −78° C. was continued for 10 min before slow rising of the temperature to 0° C. over a period of 15 min. A solid precipitate was formed. The mixture was cooled to −78° C., a 1.6 M n-BuLi solution in Hex (3.71 ml, 0.59 ml) was added, then it was stirred 10 min before addition of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (836 mg, 3.9 mmol) in THF (5 ml). After stirring 30 min at −78° C. the solution was slowly warmed to room temperature. Sat. aq. NH4Cl sol. (5 ml) was added, the mixture was diluted with EtOAc (100 ml) and washed with sat. aq. NH4Cl sol. (100 ml), sat. aq. NaHCO3 (2×100 ml) and brine (100 ml). After drying (Na2SO4) and evaporation of the solvent, the crude product was purified by chromatography (amino modified silica gel, Hept to EtOAc) to yield 971 mg (79%) of a brown oil. MS (m/z): 316.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cu](C#N)[C:32]#[N:33].N.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:32]#[N:33])[CH:29]=1
Reactant: N#C[Cu]C#N
Reactant: CCOc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(=O)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 80 °C
Yield: 51 %

Procedure:
To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N,N-dimethyl formamide (25 ml) under N2 was added copper cyanide. The resultant suspension was refluxed for 1 hour. The reaction was monitored by TLC and checked for the completion. Heating was discontinued and the reaction mixture was cooled down to 80° C. Ice water (15 ml), 25% aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove the solids. From the filtrate organic layer was separated. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude material dried at 60° C. under high vacuum then purified by column with ethyl acetate as eluent to provide the product (3 g, 51%) as an off white solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 70/30, 30 min elution) tR 23.70 min, 99.4% purity; 1H NMR (400 MHz, CDCl3) δ8.10 (t, J=2.9 Hz, 1 H), 8.06 (t, J=2.7 Hz, 1 H), 8.04 (m, 1 H), 7.85 (t, J=2.5 Hz, 1 H), 7.83 (m, 1 H), 7.81 (d, J=1.8 Hz, 1 H), 7.95 (d, J=1.6 Hz, 1 H), 7.37 (s, 1 H), 7.65 (t, J=7.8 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 6.41 (s, 1 H), 5.94 (s, 2 H), 2.88 (m, 1 H), 2.24 (s, 3 H), 0.86 (dd, J=6.9, 6.1 Hz, 2 H) 0.61 (m, 2 H) ppm; 13C NMR (400 MHz, CDCl3) δ86.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8 ppm.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:35]([CH3:37])[CH3:36])/[CH:26]=[C:27](/[S:29]([O:32]CC)(=[O:31])=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:35]([CH3:37])[CH3:36])/[CH:26]=[C:27](/[S:29]([OH:32])(=[O:31])=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:35]([CH3:37])[CH3:36])/[CH:26]=[C:27](\[S:29]([OH:32])(=[O:31])=[O:30])/[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOS(=O)(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC(C)=O
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(/C)S(=O)(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)S(=O)(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-(ethoxysulfonyl)-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (30 mg, 0.046 mmol, from Example 65) in acetone (2 mL) is treated with tetrabutylammonium iodide (20 mg, 0.055 mmol). The reaction mixture is refluxed for 7 h, and then stirred at room temperature overnight. The solvent is removed. The residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile) to give 12 mg (28%) of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-1-isopropyl-3-sulfobut-2-enyl]N1,3-dimethyl-L-valinamide as a white solid and 2 mg of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2Z)-1-isopropyl-3-sulfobut-2-enyl]-N1,3-dimethyl-L-valinamide
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(C)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
Solutions of methyl 3-(4-methylpiperazin-1-yl)-2-phenylquinoxaline-6-carboxylate (249.7 mg, 0.55 mmol, 1.00 equiv.) in THF/MeOH (1:1) (20 mL) and sodium hydroxide (138 mg, 3.45 mmol, 5.00 equiv) in water (1.5 mL) were placed in a 50-mL round bottom flask, stirred for 3 hrs at 30° C. in an oil bath, concentrated under vacuum, and washed with DCM. This resulted in 90 mg (45%) of 3-(4-methylpiperazin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>O1CCCC1>[C:27]([NH:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 3 (150 mg, 0.435 mmol) in acetic anhydride (0.24 mL, 2.54 mmol) was heated in tetrahydrofuran (2 mL) at 40° C. overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.68 (s, 1H), 8.53 (dd, J=4.6 Hz, 1.5 Hz, 1H), 8.06 (m, 2H), 7.91 (dd, J=8.1 Hz, 1.3 Hz, 1H), 7.7–7.78 (m, 4H), 7.36–7.45 (m, 3H), 1.97 (s, 3H), 1.29 (s, 9H); MS (ESI30 ) m/z 388 (M+H)+.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1.O.Cl>CC(O)=O>[CH3:3][C:4]1([CH3:31])[O:9][C:8](=[O:10])[CH:7]([CH:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[O:1])=[CH:17][CH:16]=2)[C:12]#[C:13][CH3:14])[C:6](=[O:30])[O:5]1
Reactant: OO
Reactant: CC#CC(c1ccc(SCc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC#CC(c1ccc(S(=O)Cc2ccccc2C)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
Hydrogen peroxide (20 μL, 0.05 mmol) was added to a 0° C. solution of 28.3 (20 mg, 0.05 mmol) in AcOH (2 mL). The reaction was stirred at 80° C. for 1.5 hours, then cooled to room temperature and stirred for 16 hours. The reaction mixture was poured into cold water and the resulting solution was acidified to pH=2 with 6N HCl(aq). The aqueous layer was extracted with ethyl acetate and sec-butanol. The combined organic layers were concentrated to yield 10 mg (50%) of 2,2-Dimethyl-5-[1-(4-o-tolylmethanesulfinyl-phenyl)-but-2-ynyl]-[1,3]dioxane-4,6-dione (29.1). LC/MSD m/e: 383.0 (consistent with di-acid-H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[C:16](=[O:18])[CH3:17].[H][H]>CC(O)C>[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[C@@H:16]([OH:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Temperature: 40 °C
Reaction time: 21 h
Yield: 100 %

Procedure:
In an autoclave, 3.22 mg of RuBr2[(S,S)-xylskewphos](3,5-Me2pica) (3.39×10−3 mmol, S/C=1000) and 7.62 mg of potassium tert-butoxide (6.79×10−2 mmol) are placed, replaced with argon gas. Under argon gas flow, 0.5 mL of 2′,6′-dichloro-3′-fluoroacetophenone (3.39 mmol, from Jiangxi Jixiang Pharmachemical) and 2.9 mL of 2-propanol are added while measuring with syringe, pressurized with hydrogen to 10 atm., stirred at 40° C. for 21 hours, and the reduction of hydrogen pressure was confirmed and (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol was obtained at 100% yield. The optical purity measured by HPLC (DAICEL CHRALPAK AD-RH, acetonitrile/water=25/75, 0.5 mL/min, 25° C., 220 nm, the retention time of each enantiomer: (S): 56.1 min, (R): 64.5 min) was 98.5% ee.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].CO.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Si:23]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@:2]([F:1])([CH3:18])[C@@H:6]1[OH:7])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2′-deoxy-2′-fluoro-2′-C-methyluridine (3, 81.1 g, 312 mmol) in dry pyridine (750 mL) was added drop-wise a solution of TBDMSCl (103.19 g, 685.6 mmol) in dry pyridine (500 mL) over a period of 45 min at ambient temperature. The reaction was allowed to stir at ambient temperature for 24 h. Methanol (85 mL) was added to the reaction mixture and it was allowed to stir for 10 min and then the solvents were distilled off under reduced pressure. Hot water (45° C.) (1 L) was added to the reaction mass and the mixture extracted with ethyl acetate (2×500 mL), washed with water (1×500 mL). The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off and the residue obtained was co-evaporated with toluene (2×500 mL) to give crude 9 as a white foam. Yield=116.9 g (quantitative). 1H NMR (CDCl3, 300 MHz): δ 0.1 (s, 6H), 0.91 (s, 9H), 1.22 (d, 3H, J=21 Hz), 2.50 (s, 2H), 3.75-4.05 (m, 4H), 5.54 (d, 1H, J=9 Hz), 5.73 (s, 1H), 6.0 (d, 1H, J=18 Hz), 7.81 (d, 1H, J=9 Hz), 8.57 (br, s, 1H), 11.1 (s, 1H).
Reaction SMILES: FC1C=C(C=CC=1F)CN1C(=[O:16])C2C(=CC=C(I)C=2)N(C)C1=O.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]#[CH:42])=[CH:36][CH:35]=1.O>CN(C=O)C.[Cu]I>[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:16])[C:41]#[CH:42])=[CH:36][CH:35]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: Cn1c(=O)n(Cc2ccc(F)c(F)c2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(O)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.5 g (1.06 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.52 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.15 g (1.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent).