Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C>CC#N>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:18]#[N:19])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)OCCC2=O
Solvent: CC#N
Product: COc1ccc2c(c1)OCC=C2C#N

Procedure:
7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN) (7 ml), CH3CN (10 ml) and a catalytic amount of ZnIhd 2 and refluxed for 2 hrs. The reaction was cooled, evaporated to dryness, then isopropyl alcohol saturated with HCl(g) (100 ml) was added and this solution refluxed 2 hrs. The reaction was cooled, evaporated to dryness, and saturated aqueous NaCl added. This was then extracted with CH2Cl2, the organic layer separated, dried (Na2SO4), filtered and evaporated affording 7.1 g of product IR(CHCl3) 2218 cm-1 :
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC(OC)=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].COC1C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:24]=[C:25]([CH2:27][CH3:28])[CH:26]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CCc1cc(NC(=O)c2nnnn2Cc2ccc(OC)cc2)c(O)c(C(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCc1cc(NC(=O)c2nnn[nH]2)c(O)c(C(C)=O)c1
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
A solution of 3'-acetyl-5'-ethyl-2'-hydroxy-1-(4-methoxybenzyl)-1H-tetrazole 5-carboxanilide (10.0 g) and methoxybenzene (10.0 g) in trifluoroacetic acid (150 ml) was heated at reflux for 45 minutes, and then the solvent was removed in vacuo. The residue was stirred with diethyl ether (100 ml) for 20 minutes, and the precipitated solid was filtered off and recrystallised from a mixture of dimethylformamide and water to give 3'-acetyl-5'-ethyl-2'-hydroxytetrazole-5-carboxanilide (6.5 g), m.p. 239°-242° C. (with decomposition).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 58.8 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF was added 720 mg of 4-methoxybenzyl chloride and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from ethanol gave 950 mg of 6-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 196°-198° C., colorless needles.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>C1COCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(SC)cc1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The ketone from Step A (180 mg) in THF (2 ml) was added to a solution of lithium diisopropylamide (1.1 mmole) in THF (3 ml) at -78° under N2 atmosphere. After 15 minutes methyl bromoacetate (100 μl) was added and the mixture was warmed to ambient temperature and stirred 12 hours. The mixture was poured into water (15 ml) and conc. HCl (2 ml), extracted with CH2Cl2 and the extracts were dried (Na2SO4) evaporated to dryness and the residue purified by chromatography on silica gel to provide the title compound as an oil. NMR (CDCl3): 1.2 (3H, d), 2.55 (3H, s), 2.3-3.1 (2H, m), 3.65 (3H, s), 3.95 (1H, m), 7.3 (2H, d), 7.95 (2H, d).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.P([CH:28]1[CH2:33][CH2:32]CCC1)(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:32]1([C:2]2[C:11]([O:12][CH3:13])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([CH3:14])=[N:9]3)=[CH:4][CH:3]=2)[CH2:33][CH2:28]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: COc1c(Br)ccc2ccc(C)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OB(O)C1CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C2CC2)ccc2ccc(C)nc12
Temperature: 25 °C
Yield: 895.1 %

Procedure:
A solution of 7-bromo-8-methoxy-2-methylquinoline (1.00 g, 3.97 mmol), Pd(OAc)2 (0.045 g, 0.198 mmol), P(Cy)3 (0.122 g, 0.44 mmol) and cyclopropylboronic acid (0.68 g, 7.93 mmol) in toluene (4 mL) and water (0.4 mL) was stirred at 100° C. for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 7-cyclopropyl-8-methoxy-2-methylquinoline (0.84 g, 99%) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[C:13]([NH:16][CH2:17][C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:17][C:18]1([CH3:19])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:20]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:15])[CH3:14]
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CC(=O)CNC(C)=O
Solvent: c1ccccc1
Product: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tryptophol (3.86 g; II, R2, R3, R4, R5, R6 = H and X1 =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O.H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is addded and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. Rf values of the amide and tryptophol are equal.
Reaction SMILES: [C:1]([N:6]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].C(O[CH:21]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)(=O)C>C1C=CC=CC=1>[CH:23]1[C:22]2[CH:21]([N:14]3[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH3:8])[CH2:16][CH2:15]3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)N(CC)CCC1CCNCC1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CCOC(=O)N(CC)CCC1CCN(C2c3ccccc3Oc3ccccc32)CC1

Procedure:
Reaction of the above prepared 4-[2-(N-carboethoxy-N-ethylamino)ethyl]piperidine with 9-acetoxyxanthene in benzene by the procedure of Example 3 gives 1-(9-xanthenyl)-4-[2-(N-carboethoxy-N-ethylamino)ethyl]piperidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
2-chloro-5-fluoropyridine (5.00 g, 38.01 mmol) was combined with hydrazine monohydrate (15 mL, 303.0 mmol) in a Teflon® lined reactor. The reaction was purged with argon gas and sealed, then heated to 200° C. overnight. Following overnight heating, the reaction mixture was evaporated to solids under reduced pressure, and then dissolved in water containing NaHCO3. The mixture was transferred to a reparatory funnel, and extracted 4 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to residue under reduced pressure, followed by purification by flash column chromatography eluting with 5% MeOH 0.5% NH4OH in DCM to give the desired 5-fluoro-2-hydrazinylpyridine (1.50 g, 31% yield). MS APCI (+) m/z 128.0 (M+1) detected.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:25]COC(C)=O>C1COCC1>[C:1]([N:8]([C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:25])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (R)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol) and MeI (189 mg, 1.34 mmol) in THF (12 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 200 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17]N(CN(C)C)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[C:13](=[CH2:17])[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: CN(C)CN(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=C1CCc2nc3ccccc3c(N)c2C1=O

Procedure:
In 25 ml of trifluoroacetic acid cooled in ice was dissolved 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. To the solution was added dropwise 6.70 ml (2.09 eq) of bisdimethylaminomethane over 5 minutes and thereafter the mixture was maintained at 90°-100° C. for 5 hours during which the starting material was converted to a mixture of intermediate and exo-methylene products. The reaction mixture was poured into ice/NaOH to make it basic and the precipitate was extracted with several portions of 5:1 dichloromethane/MeOH. The combined extracts were evaporated to a residue. The residue was refluxed in toluene for 5 hours during which the intermediate was converted to the end product. The reaction mixture was evaporated to a residue which was purified by chromatography on silica gel (EtOAc) to yield about 2 g of a solid. This was recrystallized from dichloromethane/EtOAc to yield 1.79 g (34%) of product as a solid, melting point 192°-193° C.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([F:37])[C:18]3[N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][C:23](Br)=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:97]1[CH2:102][CH2:101][O:100][CH2:99][CH2:98]1>>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([F:37])[C:18]3[N:19]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][C:23]([N:97]2[CH2:102][CH2:101][O:100][CH2:99][CH2:98]2)=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(Br)ccc2N3C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(N4CCOCC4)ccc2N3C(=O)OC(C)(C)C)CC1

Procedure:
To a stirred solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-fluoro-7-bromo-10-Boc-phenothiazine (1.1 g, 2.0 mmol) in toluene (10 mL) Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (31 mg, 0.018 mmol), Cs2CO3 (652 mg, 2.0 mmol) and morpholine (348 mg, 4.0 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:30]1([CH2:42][C:43]([NH2:45])=[O:44])[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1>>[C:30]1([C:42]2[C:43](=[O:44])[NH:45][C:3](=[O:2])[C:4]=2[C:6]2[C:14]3[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Product: CC(C)[Si](OCCCc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)propyl)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li][CH2:20]CCC.C[Si](C)(C)[O:26][C@@H:27]1[C@@H:32]([O:33][Si](C)(C)C)[C@H:31]([O:38][Si](C)(C)C)[C@@H:30]([CH2:43][O:44][Si](C)(C)C)[O:29][C:28]1=[O:49].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:28]2([O:49][CH3:20])[C@H:27]([OH:26])[C@@H:32]([OH:33])[C@H:31]([OH:38])[C@@H:30]([CH2:43][OH:44])[O:29]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(Br)cc1Cc1ccc(C2CC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(C4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirred solution of 4-bromo-1-chloro-2-(4-cyclopropylbenzyl)benzene (6.6 g, 20.5 mmol) in dry THF/toluene (90 mL, 1:2) at −78° C. under argon was added dropwise n-BuLi (9.84 mL, 24.62 mmol, 2.5 N in hexane) over 10 minutes, and then the mixture was stirred for 30 minutes at −70° C. A solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (12.4 g, 26.6 mmol) in anhydrous toluene (30 mL) was added dropwise over 5 minutes, and the reaction solution was stirred for 1 hour at −65° C. The reaction was quenched by addition of saturated aq. ammonium chloride (100 mL) at 0° C., the organic layer was separated, and the aqueous layer was extracted with toluene (30 mL). The combined organic phases were concentrated under reduced pressure, and the residue was dissolved in methanol (200 mL). The solution was cooled with an ice/water bath to 0° C., and then 4-methylbenzenesulfonic acid hydrate (2.43 g, 15.4 mmol) was added in one portion. The resulting solution was stirred at 25° C. for 18 hours. LC-MS showed the reaction was complete. Saturated aqueous sodium bicarbonate (50 mL) was added, and the mixture was concentrated under reduced pressure to remove most of the methanol. The residue was treated with water (100 mL) and ethyl acetate (100 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give crude product 56 as a white solid (8.0 g, 89.6% yield), which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH:14]1[O:18][CH2:17]CC1.CC(C)([O-])C.[Na+].C1COCC1.N1C=CN=C1.O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:14]2[CH2:17][O:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: CC1CCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H]2CO2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
(S)-3-(S)-1,2-Dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (230 g, 990 mmol, 1.0 eq.) was combined with MeTHF (4.9 kg, 57 mol) and cooled to 0° C. 2.0 M Sodium t-butoxide in THF (994 mL, 2.0 eq.) was added drop wise over 20 minutes. The mixture was stirred at −1° C. for 15 minutes, then cooled to −7° C. p-Tolylsulfonyl)imidazole (243 g, 1.1 mol, 1.1 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with cold H2O (5.7 kg, 320 mol). Hexanes (1.8 kg, 21 mol) was added and the mixture was warmed to 23° C. and stirred for about 30 minutes. The layers were allowed to settle, the phases were separated, and the reaction vessel was rinsed with MeTHF (100 mL). The organic layer (˜8 L) was removed and stored at 5° C. overnight, then filtered through Na2SO4 and concentrated at 60 torr to 30 torr with a water bath at 25° C. to yield the title compound (220 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]([CH3:14])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C(=O)O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 15 °C

Procedure:
3-tert. Butyl-6-methyl salicylic acid (62.4 g 0.3M) was suspended in glacial acetic acid (300 ml) and cooled to 15°C. Concentrated nitric acid (22.5 ml) was added dropwise with stirring at such a rate that the temperature was maintained at approx. 10°-15°C. The mixture was stirred for 1 hour at this temp. and then poured onto crushed ice. A precipitate formed which was filtered off, washed with benzene and finally recrystallized from acetonitrile to give 3-tert. butyl-5-nitro-6-methyl salicylic acid (30.6 g) m.p. 225°-226°(dec)
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21]CC)=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.CN(C)C(=O)C.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][NH:37]1.[OH-].[Na+]>CCO.C1COCC1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:37]3[CH2:38][CH2:39][C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:36]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:19]([OH:21])=[O:20])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc2nc(N3CCc4ccccc4C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (25 mg, 50 μmol), N,N-dimethylacetamide and 1,2,3,4-tetrahydroisoquinoline (50 μL). The reaction was heated to 100° C. for 30 min. Then THF (1 mL), EtOH (absolute, 500 μL), and 5 M aq NaOH (500 μL) were introduced. The reaction was heated for another 30 min at 100° C. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C29H29ClN2O3S: 521.2, 523.2 (M+H+); Found: 521.2, 523.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.71-7.47 (m, 4H), 7.38 (s, 1H), 7.30-7.22 (m, 4H), 5.17 (s, 1H), 4.79 (s, 2H), 3.84 (t, J=6.0 Hz, 2H), 3.09 (t, J=6.0 Hz, 2H), 2.54 (s, 3H), 0.96 (s, 9H).
Reaction SMILES: [C:1]1(=[O:15])[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[C:3](=[O:14])[NH:2]1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:2]1[C:3](=[O:14])[C:4]2[CH:5]=[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]3=[CH:8][C:9]=2[C:1]1=[O:15])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Product: CCOC(=O)CN1C(=O)c2cc3ccccc3cc2C1=O

Procedure:
2 g (10.1 mmol) Benzo[f]isoindole-1,3-dione was reacted with bromoacetic acid ethyl ester analogously to Example D-21a. The crude product obtained was partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give 2.68 g (9.5 mmol) of product. 1H NMR (200 MHz, CDCl3) δ 8.36 (s, 2H), 8.05 (m, 2H), 7.68 (m, 2H), 4.49 (s, 2H), 4.22 (q, J=7.0 Hz, 2H), 1.29 (t, 7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4](=O)[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:3].[CH:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH2:17].[OH2:19]>C(O)(=O)C>[CH:2]([C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[N:18][C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:19])[C:12]=2[N:17]=1)([CH3:3])[CH3:1]
Reactant: NC1CCCCC1N
Reactant: CC(C)C(=O)C(=O)C(C)C
Reactant: O
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)C(=O)CCC2

Procedure:
8.7 g of 2,5-dimethyl-3,4-hexanedione and 11.2 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 30 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 6.8 g of the title compound as a colorless oil.
Reaction SMILES: C(OCC)(=O)C.[C:7]([O:11][C:12]([NH:14][C:15]1([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[H][H]>[C].[Pd].CO>[C:7]([O:11][C:12]([NH:14][C:15]1([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C=CC1(NC(=O)OC(C)(C)C)CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1(NC(=O)OC(C)(C)C)CCOCC1

Procedure:
In the ethyl acetate (30 mL) and methanol (12 mL) mixed solution of ethyl 3-(4-t-butoxycarbonylamino-tetrahydro-pyran-4-yl)-acrylate which had been obtained in 3), 5% palladium carbon catalyst was added at room temperature. The reaction mixture was stirred under the hydrogen gas stream at room temperature for 75 minutes. The palladium catalyst was removed by filtration with Celite, and the filtrate was concentrated and dried up to give colorless oily matter (2.69 g).