Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)OCC3C=CC=CC=3)=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1.[C:22]([O:25][C@H:26]([CH2:32]Cl)[CH2:27][NH:28][C:29](=[O:31])[CH3:30])(=[O:24])C.O(C(C)(C)C)[Li]>CN(C=O)C.CO.CC(O)=O>[CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:32][C@H:26]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:25][C:22]3=[O:24])=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1
Reactant: O=C(Nc1ccc2c(c1)CCSC2)OCc1ccccc1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: [Li]OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCSC3)C(=O)O1
Temperature: 25 °C
Reaction time: 32 h
Yield: 72.8 %

Procedure:
A solution of phenylmethyl (3,4-dihydro-1H-2-benzothiopyran-6-yl)carbamate (Step 3, 2.55 g, 8.52 mmol), (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (Tet. Lett. 1996 37 (44) 7737-7740; 3.30 g, 17.03 mmol) and MeOH (0.690 mL, 17.03 mmol) in dry DMF (5.6 mL) under N2 is treated with LiOtBu (1M in hexanes, 25.5 mL, 25.5 mmol) dropwise over 2 hrs, and the resulting biphasic mixture is stirred at ambient temperature for 32 hrs. The mixture is then cooled in an ice bath and treated with glacial HOAc (975 μL), and MeOH (10 mL) is added and the layers are separated. The hexane layer is reextracted with 20% H2O/MeOH (20 mL), and the combined MeOH/H2O phase is diluted with H2O (40 mL) and extracted with EtOAc (3×40 mL). The combined EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (0.5/99.5-3/97). Those fractions with an Rf=0.27 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the product triturated with EtOAc/Et2O to give 1.90 g (73%) of the title compound as an off-white solid, mp 112-114° C. (decomp.). MS (ESI+) for C15H18N2O3S m/z 307 (M+H)+; [α]25D=−24° (c 0.80, DMSO).
Reaction SMILES: [P:1]([O-:23])([O-:22])([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[OH-].[K+:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)[Cl:27]>>[P:1]([O-:22])([O:23][CH2:29][CH:28]([OH:30])[CH2:26][Cl:27])([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[K+:25]
Reactant: CCCCCCCCCCCCCCCCC=COP(=O)([O-])[O-]
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC=COP(=O)([O-])OCC(O)CCl
Temperature: 80 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
20 g (0.052 moles) of monooctadecenyl phosphate having a purity of 90% (AV1=165.0, AV2=323.2) was charged into a reactor, to which 58.8 ml of 1N potassium hydroxide aqueous solution was added and agitated at 80° C. to obtain uniform solution, at which the acid value of the reaction system was 40.2. While keeping the reaction system at 80° C., 24.1 g (0.26 moles) of epichlorohydrin was gradually dropped, followed by agitation at the temperature for 6 hours. The acid value of the reaction system was approximately zero, revealing that the reaction rate of the phosphoric monoester was almost 100%. The resulting product was collected by HPLC and the solvent was distilled off under reduced pressure to obtain 16.9 g (yield 67.8%) of potassium octadecenyl 2-hydroxy-3-chloropropyl phosphate.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][C@@H:37]6[CH2:39][C@H:34]5[CH2:35][NH:36]6)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:40]([N:36]1[CH2:35][C@@H:34]2[CH2:39][C@H:37]1[CH2:38][N:33]2[CH2:32][C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:2][CH2:3]4)(=[O:5])=[O:6])=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4C[C@@H]5C[C@H]4CN5)cn3)[nH]2)cc1)C1CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of (1S,4S)-2-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane (29.0 mg) in dichloromethane (5 mL) were added acetyl chloride (6 μL) and triethylamine (23 μL) under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (10.0 mg, yield 32%) as a colorless amorphous solid. MS: 589 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(F)ccc1F
Product: Fc1ccc(F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5 difluorobenzaldehyde. MS (ESI) m/z 505.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cn1
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cn1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(6-methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16n and amine 14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:16][NH:17][CH3:18].[C-:19]#[N:20].[Na+]>C1COCC1.CO.O>[CH3:16][N:17]([CH3:18])[CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)[C:19]#[N:20]
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)C(C#N)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2-(4-Fluorophenyl)oxazole-4-carbaldehyde (1.0 g, 5.23 mmol) was dissolved in THF-MeOH (20 mL, 1:1 v/v). This solution was added to a solution of dimethylamine hydrochloride (470 mg, 5.7 mmol) and NaCN (640 mg, 13.0 mmol) in water. The resulting reaction mixture was stirred at room temperature for 2 h, and then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.0 g, crude) as a brown oil, which was used without further purification. MS (ESI) m/z: Calculated for C13H12FN3O: 245.10. found: 245.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]2[C@@H:30]3[C@@H:26]([O:27][C:28]([CH3:32])([CH3:31])[O:29]3)[C@H:25]([N:33]3[C:37]4[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]5[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=5[O:52][CH3:53])[C:36]=4[CH:35]=[CH:34]3)[CH2:24]2)[CH3:21])[CH2:17]1.C(O)(=O)C>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH:18]([N:20]([CH2:22][C@@H:23]4[C@H:30]5[O:29][C:28]([CH3:32])([CH3:31])[O:27][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH:42][CH2:43][C:44]7[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=7[O:52][CH3:53])[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH3:21])[CH2:19]3)=[N:1][C:2]=2[CH:7]=1)([CH3:10])([CH3:9])[CH3:11]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 86.6 %

Procedure:
A solution of N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (0.24 g, 0.32 mmol) in Acetic acid (5 ml, 90 mmol) was stirred overnight at 60° C. The volatiles were removed in vacuo and remaining residue partitioned between Na2CO3 (2N) and DCM. The aqueous layer was extracted 3× with DCM and the combined organics dried with MgSO4, filtered and concentrated The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 94:6) to yield the desired compound (0.20 g) as a solid.
Reaction SMILES: C(O)[CH2:2][OH:3].O.O.O.O.[C:9]([O-:12])(=[O:11])[CH3:10].[Mg+2].[C:14]([O-])(=O)C.O=[Sb]O[Sb]=O.C(C1C=[C:29](OC)[CH:30]=[C:31]([C:34]([CH3:37])(C)C)[C:32]=1[OH:33])(C)(C)C>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:32]([O:3][CH3:2])(=[O:33])[C:31]1[CH:30]=[CH:29][C:10]([C:9]([O:12][CH3:14])=[O:11])=[CH:37][CH:34]=1
Reactant: OCCO
Reactant: CC(=O)[O-]
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Co+2]
Agent: O=[Sb]O[Sb]=O
Agent: [Mg+2]
Solvent: O
Product: COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
93.1 g(0.48 mol) of dimethyl terephthalate, 10.68 g(0.02 mol) of dimethyl 6,6'-(isophthaloyl-dioxy)-di-2,2'-naphthoate, 68.2 g(1.1 mol) of ethylene glycol were polymerized in the presence of 87 mg of magnesium acetate tetrahydrate and 34 mg of cobalt acetate tetrahydrate. At the temperature of 250° C., 45 mg of antimony trioxide and 300 mg of 3,5-di-tert.-butyl-4-hydroxy anisole were added. The resulting polymer had an intrinsic viscosity of 0.55 dl/g, a Tg of 81° C. and a Tm of 232° C.
Reaction SMILES: [F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5]OC1C=CC=C(C)C=1S([O-])(=O)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH2:5][NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)C(F)(F)CCCNCc1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
4,4,5,5,5-Pentafluoropentyloxytoluenesulfonate (1 g, 3 mmol) was dissolved in acetonitrile (10 ml). Benzylamine (646 mg, 6 mmol) and potassium carbonate (829 mg, 6 mmol) were added. The mixture was refluxed for 10 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (dichloromethane:ethyl acetate=19:1) to give 590 mg (yield: 74%) of the title compound as a pale yellow liquid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([Cl:24])=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[C:9]1=[O:25])(C)(C)C.C1(O)C=CC=CC=1.C([O-])(=O)C.C(#[N:40])C>O>[ClH:24].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([NH2:40])=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Reactant: CC#N
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Solvent: O
Product: Cl
Product: Nc1ccnc2cc(CN3CC[C@H](N)C3=O)ccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
[1-(4-chloroquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (250 mg, 0.665 mmol), phenol (626 mg, 6.65 mmol), and anhydrous acetate (513 mg, 6.65 mmol) are combined and heated at 100° C., with reflux apparatus, under nitrogen overnight. Then the mixture is cooled to room temperature, and acetonitrile (20 mL) and water (20 mL) are added. The solution separates into 2 phases (both containing product), which are concentrated to dryness, and separately purified by reverse phase preparation HPLC with gradient elution 20-40% acetonitrile/water (0.1% trifluoroacetic acid). The product fractions from each run are combined, the solvents are removed in vacuo, and the residue dried under high vacuum overnight. The [1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester intermediate is dissolved in methanol, and cooled to 0° C., whilst bubbling dry HCl(g) through the solution until saturated. The reaction mixture is left at room temperature for 2 hours, and concentrated in vacuo. The residue is washed with ether to give the pure product as a colorless powder (170 mg, 0.516 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O-])=O.Cl.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1N1CCNCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1N1CCNCC1

Procedure:
A mixture of 1-nitro-2-piperazinyl-4-pyrrolidinylbenzene (4.57 g), ethanol (110 ml), hydrochloric acid (1.2N, 6 ml) and palladium on carbon (10%, 1 g) is exposed to hydrogen 51 psi at 20°-25° in a Parr flask. After 16 h (49 psi total uptake) the mixture is filtered. Basic workup (chloroform, potassium carbonate) and column chromatography silica gel (50 g) eluting with chloroform/methanol (4/1) gives the title compound as an oil. IR (nujol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm-1 ; NMR (CDCl3) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 δ; MS (electron impact) 246, 204 and 189.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([NH:19][C:20]([NH:7][C:6]1[CH:8]=[C:2]([Br:1])[C:3]([F:10])=[CH:4][C:5]=1[F:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(Br)c(F)cc1F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)c(F)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 5-bromo-2,4-difluoro aniline (1.0 g, 4.81 mmol) in acetone (25.0 mL) was added drop wise benzoyl isothiocyanate (0.71 mL, 5.29 mmol). The resulting reaction mixture was allowed to stir at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue was washed with hexane and ether to get the title compound (1.70 g, quantitative yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.02-7.06 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 7.91 (d, J=7.60 Hz, 2H), 8.67 (t, J=7.60 Hz, 1H), 9.15 (br s, 1H) and 12.65 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CC(C)([O-])C.[K+].[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C=O)C.C(OCC)(=O)C.O.[I-].[K+]>[CH3:21][O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:5]1=2
Reactant: COC(=O)CCCCCBr
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCCCCn1c2c(c3ccccc31)CN(C)CC2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (17) (0.50 g, 2.7 mmol) was placed under argon and dissolved in 5 mL of anhydrous DMF. Potassium tert-butoxide (0.32 g, 2.8 mmol) was dissolved in 3 mL of anhydrous DMF and added slowly to the reaction at room temperature. The reaction turned from orange to dark brown. After 15 min, 6-bromohexanoic acid methyl ester (0.56 g, 2.7 mmol) and 5 mg of potassium iodide were added to the reaction at room temperature. The reaction was heated to 80° C. for 2 h upon which a precipitate formed and the reaction turned from dark brown to dark orange. The reaction was then diluted with 30 mL of ethyl acetate and 30 mL of water. The organic layer was isolated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by MPCC (0-80% gradient of ethyl acetate in hexane) afforded the title compound (0.35 g, 40%) as a yellow oil. 1H NMR (400 MHz, DMSO): δ 7.46 (m, 2H), 7.17 (m, 1H), 7.06 (m, 1H), 4.46 (m, 2H), 4.10 (t, 2H, J=7.0 Hz), 3.66 (m, 2H), 3.56 (s, 3H), 3.16 (m, 2H), 3.00 (s, 3H), 2.28 (t, 2H, J=7.4 Hz), 1.66 (m, 2H), 1.55 (m, 2H), 1.29 (m, 2H). 13C NMR (100 MHz, DMSO): δ 173.7, 136.7, 131.3, 124.7, 121.9, 119.7, 118.0, 110.3, 101.8, 51.6, 51.0, 50.5, 42.9, 42.2, 33.6, 29.8, 26.1, 24.6, 19.8. ESI-HRMS (m/z): [M+H]+ calcd. for C19H26N2O2, 315.1959. found, 315.1945.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:13][C@:14]12[CH2:30][CH2:29][C@H:28]3[C@@H:19]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=43)[C@@H:18]1[CH2:17][CH2:16][C:15]2=O.C1COCC1>CO>[CH2:1]([NH:8][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:14]12[CH3:13])[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:21][CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CC[C@@H]2NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzylamine (11.2 ml) in dry methanol (75 ml) was added sequentially acetic acid (6.16 ml), estra-1,3,5(10)-trien-17-one (5.21 g) sodium cyanoborohydride (1.35 g), and THF (60 ml) under a N2 atmosphere. The resulting mixture was stirred overnight at room temperature, concentrated in vacuo, diluted with water (200 ml), and made alkaline with aqueous sodium hydroxide (50 ml). The suspension was extracted with ethyl acetate (3×200 ml) and the combined extracts were dried over MgSO4, filtered and concentrated to an oil. This product was chromatographed (300 g silica gel 0.4-4-96 Et3N-acetone-hexane, 20 ml fractions) and gave impure product in fractions 53-79 and pure product in fractions 80-135. The latter were combined and after removal of the solvent gave the title compound as crystals, mp 71°-74° C. (PLA2, diabetes)
Reaction SMILES: C(S[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([Br:16])=[C:11]([CH3:17])[N:10]=1)C1C=CC=CC=1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](OO)=O)[CH:20]=1.[O-:29][S:30]([O-:32])=O.[Na+].[Na+]>ClCCl>[CH2:25]([S:30]([C:9]1[N:14]=[C:13]([CH3:15])[C:12]([Br:16])=[C:11]([CH3:17])[N:10]=1)(=[O:32])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(SCc2ccccc2)nc(C)c1Br
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(S(=O)(=O)Cc2ccccc2)nc(C)c1Br
Yield: 94 %

Procedure:
A solution of 2-benzylthio-4,6-dimethyl-5-bromopyrimidine (5 mmol) and 85% m-chloroperbenzoic acid (15.9 mmol) in dichloromethane (100 ml) was left at room temperature for 3 days. The solution was then shaken with saturated Na2SO3 aq. (3×15 ml), saturated NaCHO3 aq. (3×10 ml) and the dried MgSO4 solution evaporated to leave the sulfone; yield 94%, m.p. 138°-139° C. (iPrOH). 1H NMR (TFA): δ2.83 (Me), 4.93 (CH2), 7.33 (Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>>[Cl:29][CH2:30][C:31]([N:15]([C:13]1[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CNc1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Product: CC(C)CN(C(=O)CCl)c1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
The product of Step A was reacted with chloroacetyl chloride using conditions similar to EXAMPLE 62 Step A to afford the title compound. HPLC/MS: 489.9 (M+1), 491.8 (M+3); Rt=4.40 min.
Reaction SMILES: [CH3:1][CH:2]1[C:19](=O)[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[BH4-].[Na+]>C1COCC1.C(O)C.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:19]=1)=[CH:6][C:7]1[C:8]([CH3:18])([CH3:17])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=Cc2cc3c(cc2C1)-c1ccccc1C3(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
In a 1000 mL round flask, 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (50 g, 190.6 mmol) was dissolved THF 400 mL and ethanol 400 mL, and then stirred. Sodium borohydride (NaBH4) (9.4 g, 247.8 mmol) was added to the reaction product in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reaction product was dissolved in 320 mL, of toluene, and then inputted to a 500 mL round flask. After that, p-toluene sulfonic acid (0.2 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 42.0 g of 2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluorene (yield: 89.42%).