Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].F[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:21])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][C:13]([O:19][CH3:20])=[CH:12][CH:11]=3>CN(C)C=O>[CH3:20][O:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:21])[C:8]1[CH:7]=[CH:6][C:5]([C:1]#[N:2])=[CH:18][C:17]=1[O:16]2
Reactant: [C-]#N
Reactant: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c3ccc(C#N)cc3oc2c1
Temperature: 100 °C

Procedure:
A mixture of finely ground sodium cyanide (1.3 g, 26.5 mmol) and 3-fluoro-6-methoxy-xanthen-9-one (2.3 g, 9.42 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. for 4 hours. Sodium cyanide (0.7 g, 14.3 mmol) was added and heating continued an additional hour. The mixture was allowed to cool to room temperature, then poured into ice water (˜150 mL). The product was collected by filtration, washed with water and air dried to give Compound 5i, 1.42 g (60%). MS: m/z 251.9 (MH+). 1H NMR (CDCl3): δ 3.96 (s, 3H), 6.91 (d, 1H, J=2.3 Hz), 7.00 (d of d, 1H, J=2.3 & 8.9 Hz), 7.61 (d of d, 1H, J=1 & 8.1 Hz), 7.79 (d, 1H, J=1 Hz), 8.24 (d, 1H, J=8.9 Hz) and 8.42 (d, 1H, J=8.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 64.5 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of methanol. The resulting mixture was under stirring at 62-67° C. in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.23 g (reaction yield: 86.5%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: O=C1CCCc2c1[nH]c1c(NS(=O)(=O)c3cccs3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.20 g) and pyridine (20 mL) was added thiophene-2-sulfonyl chloride (1.30 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.94 g, yield 86%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point>280° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:51]([O:53][C:54]([C:56]1[C:64]2[N:63]=[C:62]([NH2:65])[NH:61][C:60]=2[CH:59]=[C:58]([O:66][CH2:67][CH3:68])[CH:57]=1)=[O:55])[CH3:52]>CN(C=O)C.[Cl-].[Na+].O>[CH2:51]([O:53][C:54]([C:56]1[C:64]2[N:63]=[C:62]([NH:65][C:15]([C:7]3[N:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=4)=[O:17])[NH:61][C:60]=2[CH:59]=[C:58]([O:66][CH2:67][CH3:68])[CH:57]=1)=[O:55])[CH3:52]
Reactant: COc1cc2cnc(C(=O)O)cc2cc1OC
Reactant: CCOC(=O)c1cc(OCC)cc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)cc2[nH]c(NC(=O)c3cc4cc(OC)c(OC)cc4cn3)nc12
Yield: 63 %

Procedure:
235 mg (1.0 mmol) of 6,7-dimethoxy-isoquinoline-3-carboxylic acid and 400 mg (1.0 mmol) of HBTU were dissolved in 1.5 mL of DMF and 0.5 mL of DIEA and treated with 249 mg (1.0 mmol) of 2-amino-6-ethoxy-1H-benzoimidazole-4-carboxylic acid ethyl ester (prepared in Example 471) as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 290 mg (0.63 mmol, 63%) of 2-[(6,7-dimethoxy-isoquinoline-3-carbonyl)-amino]-6-ethoxy-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 465 (M+1)+.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Br:23][C:24]1[N:25]=[C:26](Br)[C:27]2[N:28]([CH:30]=[CH:31][N:32]=2)[CH:29]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C.O>[Br:23][C:24]1[N:25]=[C:26]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[N:28]([CH:30]=[CH:31][N:32]=2)[CH:29]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cn2ccnc2c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tri-o-tolylphosphine (1.1 g) is added to a suspension of tris(dibenzylideneacetone)dipalladium (1.65 g) in degassed toluene (50 mL) and the mixture is stirred at room temperature for 15 minutes (min). 6,8-Dibromo-imidazo[1,2-a]pyrazine (5.0 g) is then added and the mixture is stirred at room temperature for 15 minutes more. Aniline (1.52 g) is added followed by potassium t-butoxide (2.84 g) and the mixture is stirred at room temperature for 72 hr. Water (150 mL) is added and the mixture is extracted with ethyl acetate (3×150 mL), the extracts are washed with water (1×100 mL) and brine (1×100 mL), dried over MgSO4, and evaporated in vacuo to afford a gum. Trituration with diethyl ether affords (6-bromo-imidazo[1,2-a]pyrazin-8-yl)-phenyl-amine (4) as a brown solid.
Reaction SMILES: C([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:14]=3[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:17]1[C:14]2[CH2:15][C@H:16]3[C@H:11]([CH2:10][CH2:9][NH:8]3)[CH2:12][C:13]=2[CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1cccc2c1C[C@H]1[C@H](CCN1Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1C[C@@H]1NCC[C@@H]1C2
Yield: 101.8 %

Procedure:
1.7 g (5.8 mmol) of cis-(±)-1-benzyl-8-methoxy-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (9b) are dissolved in 35 mL of methanol and hydrogenated at 20° C. and 5 bars of hydrogen pressure on 0.2 g of Pd/C (10%). After 5 h the mixture is filtered over silica gel and the solvent is eliminated in vacuo. 1.2 g (100%) 10b are obtained as an oil.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[O:12]=[C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:15][NH:14]1.[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>ClCCl.C(N(CC)CC)C>[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:19]([C:18]1[C:13](=[O:12])[NH:14][N:15]=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)=[O:21]
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 19 °C
Reaction time: 3 h

Procedure:
0.02 cm3 of dimethylformamide and then 0.12 cm3 of oxalyl chloride were added to 0.3 g of 3-oxo-6-(pyridin-4-yl)-2,3-dihydropyridazine-4-carboxylic acid prepared as described in patent FR 2 481 284, dissolved in 10 cm3 of dichloromethane. The reaction medium was stirred for 3 hours at 19° C. A further 0.12 cm3 of oxalyl chloride was then added and the mixture was stirred for a further one hour at 19° C. The reaction mixture was then poured onto a solution of 10 cm3 of dichloromethane containing 0.19 cm3 of triethylamine and 0.21 cm3 of 2,4-dichlorobenzylamine. The reaction medium was stirred for 12 hours at 19° C. and then filtered through a sinter funnel, rinsed with 10 cm3 of dichloromethane, 10 cm3 of distilled water and with 10 cm3 of aqueous normal hydrochloric acid solution. After drying (10 kPa; 20° C.), 0.25 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting at 233° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=1)[CH2:3][NH2:4].[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[N:6]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: NCC(O)c1cccc(Cl)n1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
21.2 g (0.122 mol) of 2-hydroxy-2-(6-chloro-pyridin-2-yl)-ethanamine and 21 g (0.108 mol) of 1-(4-(2-hydroxyethoxy)-phenyl)-propan-2-one are dissolved in 500 ml of absolute methanol, mixed with 7.3 g (0.122 mol) of acetic acid and 7.2 g (0.114 mol) of sodium cyanoborohydride and stirred overnight at ambient temperature. Then 300 ml of methanol are distilled off in vacuo, diluted with 400 ml of water, acidified with hydrochloric acid and then extracted three times with 250 ml of methylene chloride. The aqueous phase is then made alkaline with ammonia and extracted with methylene chloride. The organic phase obtained is dried over sodium sulphate and concentrated by evaporation, and the oil obtained initially crystallises out after a short time.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 22.6 h
Yield: 38.5 %

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.2 g, 0.65 mmol) in DMF (1.3 mL) was added pyrrolidine (0.046 g, 0.65 mmol) followed by potassium carbonate (0.180 g, 1.3 mmol). The reaction was stirred at 100° C. for 22.6 h. After which, the reaction mixture is cooled to rt and water was added. The crude reaction was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoline (0.09 g, 0.250 mmol, 38.6% yield). Mass Spectrum (ESI) m/e=360.0 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([N:73]1[CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:66]([N:73]1[CH2:78][CH2:77][CH:76]([NH:79][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:75][CH2:74]1)[C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCN(Cc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 82.3 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.029 g (0.15 mmole) 1-benzyl-piperidin-4-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.051 g of N-(1-benzyl-piperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-122) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[O:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[O:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 97.2 %

Procedure:
Methyl 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoate (20 mg, 0.043 mmol) was dissolved in a mixture of THF/H2O (7/1, 3 ml) and LiOH (4.1 mg, 0.17 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1M) and the water phase washed with two portions of EtOAc (3×5 ml). After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 19 mg of 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoic acid (yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.[ClH:29].[N:30]1([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:34][CH2:33][CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:29].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.55 g. (9.37 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran are combined with 1.82 g. (9.37 mmoles) of γ-pyrrolidinobutyric acid hydrochloride and 2.06 g. (10.0 mmoles) of dicyclohexylcarbodiimide in 150 ml. of methylene chloride and stirred at room temperature for 21/2 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to give a residue which crystallized upon standing. The material is triturated with ether and filtered. Recrystallization from benzene-ether gives the product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:21]=[N:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=1[CH3:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:21]=[N:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[CH3:26])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2cnc(OC)cc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCO)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of the resulting thiourea (3.90 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.70 g, 8.89 mmol), and triethylamine (1.2 mL) in tetrahydrofuran (40 mL) was stirred at 50° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (2.20 g, 8.89 mmol, 57% in 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][C:19](=[O:27])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>C(Cl)Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][NH:10][S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:18][C:19]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)Nc2ccccc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 34 (0.106 g, 0.271 mmol) in DCM (2 ml) TFA (2 ml) was added. After stirring for 2 h at room temperature, the solvent was distilled under reduced pressure to give a brown solid. The crude residue was dissolved as obtained in 1,4-dioxane:H2O 1:1 (5 ml) and K2CO3 (0.225 g, 1.63 mmol, 6 eq) was added followed by tosyl chloride (0.056 g, 0.298 mmol, 1.1 eq) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was evaporated in vacuo to dryness. Water (10 ml) was added and the resulting white solid was separated by filtration and dried. Pure 36 was obtained without further purification (0.079 g, 0.179 mmol, 66%), mp 200-202° C. 1H NMR (400 MHz, CD3OD) δ 2.39 (3H, s, Ar—CH3), 2.56 (1H, dd, J 9.2, 14.4 Hz, H—CHCO), 2.77 (1H, dd, J 6.8, 14.4 Hz, H—CHCO), 3.06 (1H, dd, J 8.2, 13.0 Hz, H—CHNH), 3.15 (1H, dd, J 6.8, 13.2 Hz, H—CHNH) 7.03-7.07 (1H, m, CH, Ar), 7.15 (2H, d, J 8.4 Hz, 2×CH, Ar), 7.21-7.26 (4H, s, 4×CH, Ar), 7.29 (2H, d, J 8.0 Hz, 2×CH, Ar), 7.36-7.38 (2H, m, 2×CH, Ar), 7.62 (2H, d, J 8.8 Hz, 2×CH, Ar). 13C NMR (400 MHz, DMSO-d6) δ21.63 (s) (Ar—CH3), 40.73 (s) (CH2CO), 41.87 (s) (CH2CHCH2), 48.13 (s) (CH2NH), 119.79 (s) (2×CH, Ar), 123.80 (s) (CH, Ar), 127.14 (s) (2×CH, Ar), 128.80 (s) (2×CH, Ar), 129.29 (s) (2×CH, Ar), 130.23 (s) (2×CH, Ar), 130.36 (s) (2×CH, Ar), 131.80 (s) (C, Ar), 138.14 (s) (C, Ar), 139.64 (s) (C, Ar), 141.53 (s) (C, Ar), 143.20 (s) (C, Ar), 169.81 (s) (C═O). νmax (pure sample)/(cm−1) 3340 (md) (N—H), 3141 (md) (N—H), 1665 (st) (C═O), 1598 (st), 1547 (st), 1493 (md), 1444 (st), 1154 (st), 1087 (md). MS (API-ES): m/z 443 [M+H]+ (100%), HRMS (API-ES) m/z found 443.1201 [M+H]+.
Reaction SMILES: O=S1(=O)[CH2:7][CH:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.Cl.C12CC(NC1)C[O:55]2>>[C@H:3]12[CH2:8][CH:6]([N:5]([CH2:9][CH2:10][NH:11][C@:12]34[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]3[C@@H:14]3[C@@:27]([CH3:30])([CH2:28][CH2:29]4)[C@@:26]4([CH3:31])[C@@H:17]([C@:18]5([CH3:45])[C@@H:23]([CH2:24][CH2:25]4)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]4[CH2:39][CH:38]6[CH:36]([CH:37]6[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:35]=4)=[CH:20][CH2:19]5)[CH2:16][CH2:15]3)[CH2:4]1)[CH2:7][O:55]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1OC2CNC1C2
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared quantitative yield following the method described above for the preparation of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate, using racemic (1S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride as the reactant. MS: m/e 685.6 (M+H)+, 2.83 min (method 6). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.80 (br. s., 1H), 5.51-5.37 (m, 1H), 4.73 (d, J=2.0 Hz, 1H), 4.59 (dd, J=2.3, 1.5 Hz, 1H), 4.42 (s, 1H), 4.18-4.10 (m, 2H), 4.07 (d, J=7.8 Hz, 1H), 3.65 (dd, J=7.7, 1.6 Hz, 1H), 3.50 (s, 1H), 2.95 (dd, J=9.8, 1.5 Hz, 1H), 2.95-2.40 (m, 8H), 2.18 (dt, J=6.5, 3.3 Hz, 1H), 2.09-1.96 (m, 3H), 1.92-1.72 (m, 6H), 1.71 (s, 3H), 1.68-1.31 (m, 9H), 1.30-1.10 (m, 10H), 1.08-0.8 (m, 16).