Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+:5].[O-]S([O-])=O.[Na+].[Na+].[S:12]1[C:16]2[CH:17]=[C:18]([S:21](Cl)(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>O>[Na+:5].[S:12]1[C:16]2[CH:17]=[C:18]([S:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc2ncsc2c1
Temperature: 80 °C

Procedure:
To a solution of 0.72 g (8.56 mmol) of NaHCO3 and 1.08 g (8.56 mmol) of Na2SO3 (4.6 mmol) in water (4.5 mL) are added 1 g (4.28 mmol) of 1,3-benzothiazol-6-sulfonyl chloride. The reaction is heated at 80° C. for 2 h. The solvent is removed under reduced pressure. The filtrate is concentrated under reduced pressure to give 1,3-benzothiazol-6-sulfinic acid sodium salt.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([O:16][CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[CH3:17][O:16][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccccc1C)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccccc1C)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 61 %

Procedure:
2-Hydroxy-3-[methoxy-(2-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 56-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (61% yield); mp 153–154° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.39 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.67 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.95 (2H, s, NCH2), 7.2–7.3 (4H, m, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.79; H, 6.30; N, 9.58.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:32]([C:29]3[N:26]4[C:25]([S:24][CH:28]=[CH:27]4)=[N:31][CH:30]=3)=[O:33])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cnc2sccn12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cnc4sccn34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=483.0.
Reaction SMILES: [C:1]1([C:7]2([C:28]([OH:30])=[O:29])[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C@:15]3([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])[C:41](Cl)=[O:42].Cl>O1CCCC1.O>[CH3:50][O:49][C:45]1[CH:44]=[C:40]([CH:39]=[C:38]([O:37][CH3:36])[C:46]=1[O:47][CH3:48])[C:41]([N:17]1[CH2:18][CH2:19][C@:15]([CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:28]([OH:30])=[O:29])[CH2:8][CH2:9]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:16]1)=[O:42]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCNC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine (S)-3-(2-(4-phenyl-4-carboxypiperidin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (50 g, 112 mmol) and sodium bicarbonate (30 g) in tetrahydrofuran (1300 mL) and water (300 mL). Add portionwise over about 45 minutes, a solution of 3,4,5-trimethoxybenzoyl chloride (26 g, 112 mmol) in tetrahydrofuran (130 mL). After 2 hours, dilute with water (1000 mL). Adjust the pH to about 4 using concentrated aqueous hydrochloric acid to give a solid. Collect the solid by filtration and rinse with water. Triturate the solid with methanol (1300 mL) and water (1300 mL). Filter, rinse with water and dry in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:10]([OH:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH2:6][CH2:5]1>CS(C)=O>[O:11]1[CH:10]2[CH:4]1[CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=12
Reactant: O[C@@H]1c2ccccc2OCC[C@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)OCCC1OC21
Reaction time: 3 h

Procedure:
8.60 g (0.298 mole) of sodium hydride (80% dispersion in mineral oil) are introduced under argon into 320 ml of DMSO, and a solution of 243 g (0.259 mole) of trans-4-bromo-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin in 180 ml of DMSO is added dropwise at room temperature within 2.5 hours. After 3 hours, the mixture is poured onto ice/water with stirring, and is extracted 3 times with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. The remaining 44 g of oil is distilled at 67°-69° C./0.01 torr.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7](S(C)=O)[N:6]=1)([CH3:3])[CH3:2].C(NC1C(C(N)=O)=CN=C(S(C)(=O)=O)N=1)(C)C.CN1C(=O)CCC1.Cl.[NH2:42][C:43]12[CH2:50][CH2:49][C:46]([OH:51])([CH2:47][CH2:48]1)[CH2:45][CH2:44]2.CCN(C(C)C)C(C)C>>[OH:51][C:46]12[CH2:49][CH2:50][C:43]([NH:42][C:7]3[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=3)([CH2:48][CH2:47]1)[CH2:44][CH2:45]2
Reactant: CC(C)Nc1nc(S(C)=O)ncc1C(N)=O
Reactant: NC12CCC(O)(CC1)CC2
Agent: CC(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(NC23CCC(O)(CC2)CC3)ncc1C(N)=O
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To the solution of 4-(isopropylamino)-2-(methylsulfinyl)-pyrimidine-5-carboxamide and 4-(isopropylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide in NMP (from previous step, 2.8 mmol), 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (500 mg, 2.8 mmol), DIEA (1.1 g, 8.4 mmol) were added and heated at 100° C. for 3 d. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography to afford the final product (74.1 mg, 8.2% yield). 1H NMR (DMSO-d6) δ ppm 8.88 (br s, 1H), 8.31 (s, 1H), 7.5-6.5 (br s, 2H), 5.76 (s, 1H), 4:25 (s, 4.11 (brs, 1H), 2.05-1.97 (m, 6H), 1.61-1.54 (m, 6H), 1.24-1.12 (m, 6H); MS (ESI) m/z 320.2 [M+H]+; Purity=96.5% at 214 nm, Purity=97.7% at 254 nm.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][C:23]=2[F:39])=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:24][C:23]=3[F:39])=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2CC(N)=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a solution of benzyl (4-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}-3-fluorophenyl)carbamate (28.0 g, 49.6 mmol) in tetrahydrofuran (280 mL) was added trifluoroacetic acid anhydride (196 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, ethanol (140 mL) and 4N aqueous sodium hydroxide solution (40 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hr. The solvent was concentrated under reduced pressure to about 1/3, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/0→9/1) to give the title compound (10.0 g, 51%).
Reaction SMILES: N#N.[CH2:3]([O:10][C@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:35][O:36][C:37]1[CH:58]=[CH:57][C:40]([C:41](Cl)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)=[CH:39][CH:38]=1>N1C=CC=CC=1.ClCCl.CCOC(C)=O.CCCCCC.C(N(CC)CC)C>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([C:41]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH3:35])=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:18][CH2:17][C@H:14]2[O:13][C@@H:12]([N:19]3[CH:27]=[N:26][C:25]4[C:20]3=[N:21][CH:22]=[N:23][C:24]=4[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C@@H:15]2[OH:16])=[CH:47][CH:46]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[Si](C)(C)CCOc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1OCc1ccccc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OCC[Si](C)(C)C)ncnc43)[C@@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
Under the protection of N2, to a solution of 9-(2-O-benzyl-β-D-arabinofuranosyl)-6-[2-(trimethylsilyl)ethoxy]-9H-purine (1.60 g, 3.49 mmol) in 20 mL pyridine was added 4,4′-dimethoxytrityl chloride (2.13 g, 6.28 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with 100 mL dichloromethane and quenched with 100 mL saturated NaHCO3 solution. After the aqueous layer was extracted with dichloromethane (100 mL) three times, the organic layers were combined and evaporated. The residue was purified by flash chromatography (gradient: hexane with EtOAc 0-100%, with 1% triethylamine in both hexane and EtOAc) to produce 1.18 g (1.55 mmol, 44.4%) product. LCMS: for C43H48N4O7Si calculated 760.9. found 762.5 [M+H]+. 1H NMR (600 MHz, CD3CN) δ: 8.39 (s, 1H), 8.10 (s, 1H), 7.42-7.40 (m, 2H), 7.29-7.13 (m, 10H), 6.86-6.85 (m, 2H), 6.81-6.77 (m, 4H), 6.50 (d, J=5.5 Hz, 1H), 4.69-4.65 (m, 2H), 4.49-4.45 (m, 2H), 4.24-4.21 (m, 2H), 4.02 (m, 1H), 3.8 (dd, 10.4, 6.3 Hz, 1H), 3.29 (dd, J=10.4, 3.5 Hz, 1H), 1.22 (m, 2H), 0.09 (s, 1H). 13C NMR (600 MHz, CD3CN) δ: 160.82, 152.01, 142.44, 130.24, 130.21, 128.39, 128.25, 128.01, 127.86, 127.61, 127.05, 113.21, 83.56, 82.87, 82.37, 74.31, 72.54, 65.26, 63.56, 55.10, 17.27, −2.13.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:7][CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl>CCCCC>[Br:1][C:9](=[CH:8][O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CCCCOC=CC(=O)C(F)(F)F
Reactant: BrBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CCCCOC=C(Br)C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
8.0 g (0.05 mole) of bromine, dissolved in 100 ml pentane, are added dropwise to a solution of 9.75 g (0.05 mol) of 4-n-butoxy-1,1,1-trifluorobut-3-en-2-one in 50 ml of pentane cooled to -20° C. After stirring for 1 hour at -20° C., a solution of 6.0 g (0.06 mole) of triethylamine in 100 ml pentane is added dropwise at the same temperature. After being allowed to stand overnight at 25° C., the mixture is poured into ice water and acidified by means of 1N hydrochloric acid and the phases are separated. Conventional work-up gives 12.1 g of almost homogeneous crude 3-bromo-4-n-butoxy-1,1,1-trifluorobut-3-en-2-one, which is freed from the small amount of impurities by distillation under reduced pressure. Boiling point 113°-115° C./16 mbar, nD20 =1.4640.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COc1ccc(C(=O)O)cc1

Procedure:
The reaction of isobutyl bromide and ethyl 4-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 4-isobutoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, COOH); 7.85 (d, J=8.8, 2 arom. H); 6.98 (d, J=8.8, 2 atom. H); 3.80 (d, J=6.4, (CH3)2CHCH2O); 2.01 (m, (CH3)2CHCH2O); 0.96 (d, J=6.4, (CH3)2CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 166.97 (—C═O); 162.35; 131.32 (2 arom. C); 122.78; 114.22 (2 arom. C); 73.89; 27.60; 18.94.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:29])([CH3:17])[C:15](=[O:30])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
8.2 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-hydroxyestra-1,3,5(10)-trien-17-one in 86 ml of THF are stirred at RT for 2.5 h with 8.6 ml of 3,4-dihydro-2H-pyran and 820 mg of p-toluenesulphonic acid. 0.5 ml of triethylamine is then added, and the mixture is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 7.8 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-(tetrahydropyran-2-yloxy) oestra-1,3,5(10)-trien-17-one are obtained as a foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:28][O:27][C:25]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[NH:14][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[O:26]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2c1CCCC2
Temperature: 60 °C

Procedure:
A solution of Example 379A (3.04 g, 7.54 mmol) in methanol (70 mL) and distilled water (7.8 mL) was treated with lithium hydroxide monohydrate (1.58 g, 37.7 mmol), heated to 60° C. overnight, cooled to room temperature, treated with 1N HCl, and concentrated. The aqueous layer was washed with dichloromethane two times and the combined organic phases were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 388 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 14.00 (br s, 1H), 8.85 (br s, 1H), 7.83 (d, 1H), 7.73 (m, 2H), 7.64 (m, 1H), 7.13 (s, 2H), 3.63 (s, 3H), 2.67 (br s, 2H), 2.51 (br s, 2H), 1.65 (br m, 4H).
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH:6]=[C:7]([CH3:9])[CH3:8])=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]([NH:3][CH:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH:6]=[C:7]([CH3:8])[CH3:9])=[O:2]
Reactant: CC(C)=CC(C)(S)[C@H](NC=O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)=CC(C)(S)C(NC=O)C(=O)O
Yield: 96.2 %

Procedure:
1.3 kilograms of N-formyl-isopropylidene-L-penicillamine were dissolved in 4.5 liters of toluene and treated with 30 ml. of acetic anhydride. This mixture was heated for 2 hours under reflux. After cooling to room temperature the pure N-formyl-isopropylidene-D,L-penicillamine crystallized out. There were obtained 1.25 kilograms of N-formyl-isopropylidene-D,L-penicillamine having a melting point of 140°-142°C. and [α]D20 = 0°.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[CH2:7]([C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[C:11]#[N:12])[CH:8]=[CH2:9]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:7]([C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH2:13][CH:14]=[CH2:15])[C:11]([NH2:1])=[NH:12])[CH:8]=[CH2:9]
Reactant: C=CCC(C#N)(CC=C)c1cccc(OC)c1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=CCC(CC=C)(C(=N)N)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of NH4Cl (13.5 9, 251 mmol) in 170 mL toluene at 0° C. was added a 2.0 M solution of AlMe3 (126 mL, 251 mmol) dropwise. The mixture was warmed to room temperature and stirred for 4 hours. 2-Allyl-2-(3-methoxy-phenyl)-pent-4-enenitrile (38.1 g, 167 mmol) in 30 mL toluene was added and the mixture was heated to 80° C. for 48 hours. The mixture was cooled to room temperature and poured into a stirring suspension of silica gel (50 g) in 150 mL chloroform (CHCl3). After stirring for 30 minutes, the suspension was filtered and the silica gel was washed with methanol (MeOH). The remaining solution was concentrated to an oil and 80 mL acetone was added. The resulting suspension was filtered, the solution was concentrated and the resulting residue was dissolved in 1N hydrochloric acid (HCl)/MeOH (200 mL). The solution was concentrated, 200 mL ethyl ether (Et2O) was added and the resulting precipitate was removed by filtration and dried yielding 22.4 9 (49% yield) of the desired product. 1HNMR (400 MHz, CD3OD) δ 8.73, 8.58 (2 brs, 3H, NH), 7.34 (t, 1H), 6.93-6.91 (comp, 2H), 6.90-6.83 (comp, 1H), 5.56-5.44 (comp, 2H), 5.18-5.14 (comp, 4H), 3.79 (s, 3H), 2.82-2.79 (comp, 4H); MS (M+1) 245.3.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15]([C:24]2[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cn1cccc1CC#N
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2 mole) p-toluoyl chloride. The resulting solution is added dropwise to a solution of l-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooled externally with an ice bath. After the addition, the resulting solution is stirred at room temperature for twenty minutes and then refluxed for three minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p-toluoyl)-1 -methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene. Additional product is isolated from the mother liquors which are combined, concentrated in vacuo, and the resulting oily residue column chromatographed on neutral alumina using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in vacuo the first few major compound-bearing fractions (10% ether in benzene). The solids are combined and recrystallized from methanol and then from benzene-hexane, m.p. 102-105° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[I-].[Na+].CS(O[CH2:12][C:13]1[CH:14]=[C:15]([NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([O:35][C:36]4[C:37]5[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:38]=5[N:39]=[CH:40][N:41]=4)=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)(=O)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:12][C:13]1[CH:14]=[C:15]([NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([O:35][C:36]4[C:37]5[CH2:45][CH2:44][NH:43][CH2:42][C:38]=5[N:39]=[CH:40][N:41]=4)=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NCc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM, isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide (0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl 4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate is converted to desired product and the tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate left over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is added followed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C. for 2 h. The solvent is then removed and the residue diluted with EtOAc, washed with H2O, brine and the organic layer dried over Na2SO4. Following concentration the residue is separated by FCC (25-100% EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCM at rt for 1.5 h. After concentration the residue is separated by semi-prep HPLC (C-18; 10-100% I/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 525.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.95 (d, J=15.2 Hz, 2H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t, J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).