Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([OH:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1.Cl[C:27]([F:32])([F:31])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([O:25][CH:27]([F:32])[F:31])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(O)c(=O)n(C)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(OC(F)F)c(=O)n(C)c2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), sodium chlorodifluoroacetate (252 mg, 1.65 mmol), K2CO3 (70 mg, 0.51 mmol) in dioxane (4 mL) was stirred at 100° C. for 18 h. After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (16 mg, 28%) as a light pink solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H) 7.77 (d, J=2.4 Hz, 1H) 7.63 (d, J=2.4 Hz, 1H) 7.49 (d, J=2.4 Hz, 1H) 7.04 (m, 1H) 3.95 (m, 2H) 3.69 (s, 3H) 3.13 (m, 3H) 1.33-1.26 (m, 4H) 0.72-0.67 (m, 2H) 0.39-0.36 (m, 2H). LCMS (M+H)+=414.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([C:10](=[O:29])[CH2:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]=[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[O:18][C:14]=3[CH:13]=2)[C@H:7]([CH2:30][O:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=2)[CH2:6]1)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C@@H:5]1[CH2:9][N:8]([C:10](=[O:29])[CH2:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]=[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])[O:18][C:14]=3[CH:13]=2)[C@H:7]([CH2:30][O:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)[CH2:6]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC(C)=O)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](O)C[C@H]3COc3ccc(C(=O)O)cc3)cc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-((2S,4S)-4-acetoxy-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)benzoate (610 mg, 1.09 mmol) in THF (40 ml) was added 0.25N NaOH (40 ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1N HCl, followed by extraction with a chloroform-methanol (10/1) mixture. The extract was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, whereby the title compound (500 mg, 92%) was obtained as a pale pink amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:62][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=6)=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:63])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (14 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 846.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([NH:8]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(4,4-difluorocyclohexyl)(t-butoxy)carboxamide (6.51 mmol) in CH2Cl2 (20 mL) was treated with TFA (10 mL) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed with chloroform. The acidic aqueous phase was cooled at 0° C. and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2Cl2, dried, and filtered yielding the title compound which was used without further purification as a 0.3 M solution in CH2Cl2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.ClC(OCC(C)C)=O.[N:22]1([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:23][CH2:24]1)=[O:8]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Into 100 ml of dimethylformamide, 2.6 g of 3,4-dimethoxybenzoic acid and 1.65 g of 1.8-diazabicyclo[5,4,0]undecene-7 were added, then the outside of the reaction vessel was ice-cooled and stirring condition, 1.5 ml of isobutyl chloroformate was added dropwise. Then the reaction mixture was further stirred for 30 minutes, a solution of 2.6 g of 6-(1-piperazinyl)carbonyl-3,4-dihydrocarbostyril dissolved in 40 ml of dimethylformamide was added to the reaction mixture and stirred at a room temperature for 5 hours. After the reaction was completed, the solvent was removed by distillation and the residue was extracted with about 300 ml of chloroform, then washed with a diluted sodium hydrogencarbonate aqueous solution, water, a diluted hydrochloric acid and water in this order. After removal of chloroform by distillation, the residue was recrystallized from ethanol-chloroform to obtain 1.8 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10](Br)[C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:14]1([C:2]2[CH:11]=[C:10]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=3)[C:9]([NH2:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(Br)cc(Br)c2cccnc12
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Nc1c(-c2ccccc2)cc(-c2ccccc2)c2cccnc12
Yield: 175.9 %

Procedure:
According to General Procedure A, a mixture of 5,7-dibromo-8-aminoquinoline (14 g, 100 mg, 0.33 mmol), phenylboronic acid (60 mg, 0.50 mmol), CsF (150 mg, 0.99 mmol), Pd(OAc)2 (1.3 mg, 0.007 mmol) and ligand 12f (5.3 mg, 0.013 mmol) in 1,4-dioxane (2.5 mL) was heated to reflux, cooled and filtered. After evaporation of the solvent, recrystallization from Et2O/hexane gave 51g (86 mg, 88%) as colorless crystals. mp: 100-102° C. (Et2O/hexane). IR (KBr): vmax 3450, 3347, 3050, 3023, 1583 cm−1. 1H NMR (300 MHz, CDCl3): δ 8.85-8.80 (m, 1H), 8.28 (dd, 1H, J=8.4, 1.5 Hz), 7.66-7.63 (m, 2H), 7.54-7.44 (m, 6H), 7.42-7.34 (m, 4H), 5.32 (s, 2H). 13C NMR (75.5 MHz, CDCl3): δ 147.5, 140.2, 139.9, 138.3, 134.2, 130.2, 130.0, 129.2, 129.0, 128.4, 128.2, 127.2, 126.8, 126.1, 121.7, 121.2. EIMS (m/z, (%)): 296 (72), 219 (24), 86 (100), 47 (85). HRMS (EI; m/z): calcd for C21H16N2: 296.1314. Found 296.1312.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[C:10]([CH3:24])([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[C:29]([CH3:32])=[N:30][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:26]2[CH:31]=[N:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:10]([CH3:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C(C)(C)C1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a solution of tert-butyl-3,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.12 g, 6.28 mmol) in 1,4-dioxane (90 mL) were added 5-bromo-2-methyl-3-nitropyridine (1.64 g, 7.54 mmol), tetrakis(triphenylphosphine) palladium (642 mg, 0.556 mmol), potassium phosphate (4.96 g, 23.4 mmol) and water (22 mL). The reaction mixture was flushed with nitrogen gas and allowed to stir for 24 h at 80° C. The reaction mixture was filtered through a Celite® pad and washed with DCM. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl-3′,3′,6-trimethyl-5-nitro-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (1.3 g, 60%) as a white solid. LCMS (FA): Rt=2.16 min, m/z=348.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.IC.[C:14](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 80 °C
Yield: 103.3 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100% yield; 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=5)=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1.[C:45](Br)(=[O:47])[CH3:46].C(N(CC)C(C)C)(C)C>ClCCl>[C:45]([NH:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]([CH2:16][CH2:15][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][CH:7]([N:6]3[C:5]5[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=5[N:3]=[C:2]3[CH3:1])[CH2:13]4)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:18][CH2:19]2)=[O:24])=[CH:30][CH:29]=1)(=[O:33])=[O:32])(=[O:47])[CH3:46]
Reactant: CC(=O)Br
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(S(N)(=O)=O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a precooled (0° C.) solution of 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-benzene-sulfonamide (20 mg, 0.033 mmol) in dichloromethane (2 mL) was added acetyl bromide (4.2 mg, 0.034 mmol) and N,N-diisopropylethyl amine (12 μL, 0.66 mmol). The resulting mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 15-30% methanol in ethyl acetate to afford N-acetyl-4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide as amorphous solid (14 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 3H), 7.37-7.33 (m, 5H), 7.21 (br, 1H), 7.13-7.05 (m, 2H), 4.51 (t, J=8.1, 1H), 3.88 (br, 1H), 3.67-3.15 (m, 6H), 2.42 (s, 3H), 2.37-2.30 (m, 2H), 2.11-2.07 (br, 2H), 1.96-1.72 (m, 13H), 1.59 (d, J=7.4, 2H). HRMS m/z (M+H)+ calcd: 654.3114, obsd: 654.3095.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:26][N:27]1[CH:31]=[C:30](I)[CH:29]=[N:28]1>CN(C=O)C>[CH3:26][N:27]1[CH:31]=[C:30]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]2)[CH:29]=[N:28]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: Cn1cc(I)cn1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(-c2cnn(C)c2)n1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Into a solution of methyl 1H-pyrazole-3-carboxylate (10 g, 79.3 mmol) in DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol), salicylaldoxime (1.08 g, 7.93 mmol), Cs2CO3 (64.4 g, 198.4 mmol) and 1-methyl-4-iodo pyrazole (16.5 g, 79.9 mmol) were added and the mixture was stirred at 110° C. for 48 h. The reaction mixture was quenched with saturated solution of aqueous NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by flash-chromatography. Yield 2.9 g. 1H-NMR (400 MHz; DMSO-d6): δ 3.83 (s, 3H), 3.88 (s, 3H), 7.90 (s, 1H), 8.29 (d, 2H). LC-MS: [M+H]=207.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:18][C@H:19]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=1)[C:20](OC)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:11]([O:18][C@H:19]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=1)[CH:20]=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Diisobutylaluminum hydride (56.5 mL, 1.5 M in toluene) was added dropwise over 1 h to a cooled (−78° C.) solution of methyl (R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(3,5-dichlorophenyl)ethanoate (14.81 g) in toluene (150 mL) under nitrogen. The resulting colorless solution was stirred at this temperature for 1 h, before a saturated aqueous solution of Rochelle's salt (70 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature, and was then diluted with ethyl acetate. The biphasic system was filtered through celite, rinsing with water and ethyl acetate . The filtrate was separated into its two layers, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer of the filtrate were combined, washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), and concentrated to afford (2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(3,5-dichlorophenyl)ethanal as a colorless oil (13.36 g). Based on its 1H-NMR spectrum, the title compound made up ca. 50% of the oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:35]([CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[CH3:36])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)C(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Yield: 35 %

Procedure:
Following Example 91, 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N1,N1,N2-trimethylethane-1,2-diamine were reacted to give 118 (yield 35% of theoretical). MS: (ESI+) 528.2
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][F:10])[CH:8]=1.[OH-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O.O>[F:18][C:17]([O:11][C:5]1[CH:4]=[C:3]([CH2:2][F:1])[CH:8]=[C:7]([CH2:9][F:10])[CH:6]=1)([F:19])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Oc1cc(CF)cc(CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: FCc1cc(CF)cc(OC(F)(F)C(F)C(F)(F)F)c1

Procedure:
490 g of 3,5-bis-fluoromethyl-phenol were placed in 1000 ml of acetone together with 50 g of 50% by weight aqueous sodium hydroxide solution, and hexafluoropropene was introduced at 25° C. up to the saturation point. The batch was then diluted with 11 of water and the organic phase was separated off, dried and distilled to give 673 g of 3,5-bis-fluoromethyl-phenyl 1,1,2,3,3,3-hexafluoropropyl ether with a boiling point of 65° to 70° C. at 22 mbar and a refractive index nD2 of 1.3560.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][C:17]2[N:22]=[C:21]([N:23]([CH3:25])[CH3:24])[C:20]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][C:17]2[N:22]=[C:21]([N:23]([CH3:24])[CH3:25])[C:20]([CH2:26][C:27]([OH:29])=[O:28])=[CH:19][N:18]=2)=[CH:31][CH:32]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.9 %

Procedure:
To a mixture of methyl [2-(4-{[(benzyloxy)carbonyl]amino}benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.51 g, 3.48 mmol) in tetrahydrofuran (8 mL) and methanol (15 mL) was added 1N NaOH aq. (5 mL). The reaction mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure. The residue was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. This residue was dissolved with chloroform/methanol (10:1) and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residual solid was recrystallized with acetonitrile/ethanol (10:1) to give [2-(4-{[(benzyloxy)carbonyl]amino}benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetic acid (1.14 g, 78%) as a white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:5])([CH3:4])[CH3:3].[OH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:2]([C:6]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([OH:19])=[C:21]([CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:22]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(O)c(CN2CCOCC2)c1
Reactant: CC(C)(C)c1cc(Cl)ccc1OCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Cl)ccc1OCCCCNC(=O)c1ccc(O)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(2-tert-butyl-4-chloro-phenoxy)-butylamine hydrochloride (0.102 g, 0.35 mmol), 4-hydroxy-3-morpholin-4-ylmethyl-benzoic acid (0.091 g, 0.385 mmol), triethylamine (54 μL, 0.385 mmol), N-hydroxybenzotriazole (0.059 g, 0.385 mmol), EDC HCl (0.074 g, 0.385 mmol) in dry DMF was stirred for 3 h at room temperature. 20 mL of a 5% sodium bicarbonate solution was added, and the reaction was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with 10% hydrochloric acid (1×20 mL), brine (2×20 mL) and dried over sodium sulfate. The solvent was removed in vacuo, the residue was triturated with a mixture of diethyl ether and ethyl acetate. The crude product was purified by flash chromatography (Kieselgel 60H) using chloroform:methanol (10:3) as an eluent. Yield: 0.070 g (42%) 6-1. LCMS: method A, Rt: 1.80 min, M+H=475).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].C1(C)C=CC=CC=1.[OH:36][S:37]([OH:40])(=[O:39])=[O:38]>C(O)(C)C>[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[CH2:2]1[CH:1]([NH:4][C:5]2[C:6]3[N:7]=[CH:8][N:9]([C@H:20]4[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]4)[C:10]=3[N:11]=[C:12]([NH2:14])[N:13]=2)[CH2:3]1.[OH:39][S:37]([OH:40])(=[O:38])=[O:36]
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 87.8 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (6.56 g, 18.40 mmol) was slurried in a mixture of isopropanol (32.8 ml) and 10% solution of NaOH (36.1 ml, 92.0 mmol). The mixture was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and toluene (32.8 ml) was added. The layers were separated and H2SO4 96% (0.61 ml, 11.03 mmol) was added dropwise to the organic layer. This mixture was cooled to 0-5° C. and the resulting slurry filtered off. The solid was dried under vacuum at 40° C. Abacavir hemisulfate (5.42 g, 88%) was obtained as a white powder.