Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:15]([C:16]([Cl:3])=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Yield: 94.9 %

Procedure:
2 drops of dimethylformamide and 11.9 g (0.1 mol) of thionyl chloride were added to a solution of 6.0 g (0.021 mol) of methyl 2-chloro-3-hydroxycarbonyl-4-methylsulfonylbenzoate and 50 ml of dry toluene. The solution was heated under reflux for 4 hours. Removal of the solvent under reduced pressure gave 6.2 g of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate.
Reaction SMILES: COC1C=C2C(=CC=1OC)N=CC=C2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26](Cl)[CH:25]=2)=[O:23])=[CH:18][CH:17]=1.B(Br)(Br)[Br:33]>ClCCl>[Br:33][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: BrB(Br)Br
Reactant: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)c(Cl)c4)cc3)c2cc1OC
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Methoxyphenyl 4-bromophenyl ketone (1.65 g) obtained in Example 122 was dissolved in dichloromethane (20 ml), a solution of 1.0 M boron tribromide in dichloromethane (23 ml) was added while cooled in ice, and the admixture was stirred at room temperature overnight. The reaction mixture was then poured into ice water and partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and the solvent was removed by reduced-pressure distillation. The resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 1.34 g of the title compound (yield: 85%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].F[B-](F)(F)F.[NH:14]=[C:15](SC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:5]([C:4]1[NH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:2][CH:3]=1)[CH2:6][CH3:7]
Reactant: CCCC(=O)CN
Reactant: CCOC(=O)C(=N)SC
Agent: Cl
Agent: F[B-](F)(F)F
Product: CCCc1cnc(C(=O)OCC)[nH]1

Procedure:
The same operation as in Example (1b) was performed using 1-amino-pentan-2-one hydrochloride obtained in Example (46a) (about 16.8 mmol) and ethyl imino(methylthio)acetate tetrafluoroborate obtained according to a method known in the literature (J. Med. Chem., 38, 1995, 2196-2201) (about 22.4 mmol), to obtain 2.61 g of the title compound as a brown foamy substance (86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1cc(Br)ccc1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromo-2(1H)-pyridone (7.8 g, 45 mmol) in 80 mL of DMF at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.1 g, 90 mmol). The mixture was stirred at 0° C. for 45 minutes. Ethyl 2-bromopropionate (9.7 g, 54 mmol) was then added via a syringe. The reaction was warmed up to rt and let stir for 16 hours. The reaction mixture was then poured into an ice-HCl (2N) solution until pH˜2. The aqueous mixture was extracted with 2×100 mL of EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (30% EtOAc/hexane to EtOAC) to give yellow oil (9.0 g, 73% yield) as desired product. MS (ESI pos. ion) m/z (MH+): 273.9. Calc'd Exact Mass for C10H12BrNO3: 273.00.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH:33]1[CH:38]=[C:37]([CH2:39]Br)[C:36]([Cl:41])=[CH:35][CH:34]=1.[H-].[Na+]>C(#N)C.O>[Cl:41][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][N:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)[C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(CN1CCOCC1)N(Cc1ccccc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 126.9 %

Procedure:
A mixture of 0.11 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of O-chlorobenzyl bromide and 0.41 g of K2 CO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na2SO4 and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:29][O:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][S:33][C:32]=1[S:40](Cl)(=[O:42])=[O:41]>[H-].[Na+]>[CH3:39][O:38][C:36]([C:35]1[C:31]([O:30][CH3:29])=[C:32]([S:40]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:41])=[O:42])[S:33][CH:34]=1)=[O:37]
Reactant: COC(=O)c1csc(S(=O)(=O)Cl)c1OC
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1csc(S(=O)(=O)Oc2ccc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C2CCCC2)c1OC
Reaction time: 0.5 h
Yield: 64 %

Procedure:
At ambient temperature, to a stirred solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.308 g, 0.683 mmol) in N,N-DMF (3.41 mL) was added in one portion 60% NaH/mineral oil (27.3 mg, 0.683 mmol). After 0.5 h, to the reaction was added a solution of commercial 3-methoxy-4-(methoxycarbonyl)thiophene-2-sulphonylchloride (0.204 g, 0.751 mmol) in N,N-DMF (1.37 mL). After 1 h, the reaction was quenched with 1 N HCl (50 mL) combined with product from an identical experiment and extracted with 25% CH2Cl2 /EtOAc. The combined organic extracts were washed with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 15% EtOAc/pet. ether gave 0.593 g, (64%) of the title compound as a colorless solid. 1H NMR (DMSO-d6) δ 1.20-1.41 (m, 2 H), 1.43-1.83 (m, 9H), 2.44 (s, 3 H), 3.24 (quintet, 1 H), 3.85 (s, 3 H), 3.99 (s, 3 H), 7.24-7.38 (m, 4 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.21 (d, 1 H), 8.81 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:31])([CH3:30])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:20]([C:21]3[C:22](=[O:28])[NH:23][C:24](=[O:27])[NH:25][CH:26]=3)[C:15]3[N:16]=[C:17]([CH3:19])[O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH:29]=1)([CH3:4])[CH3:3].[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:32][C:33]1[N:38]=[C:37]([N:25]2[CH:26]=[C:21]([CH:20]3[C:15]4[N:16]=[C:17]([CH3:19])[O:18][C:14]=4[CH:13]=[CH:12][C:11]4[CH:29]=[C:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:30])[CH3:31])[CH:8]=[CH:9][C:10]3=4)[C:22](=[O:28])[NH:23][C:24]2=[O:27])[CH:36]=[CH:35][N:34]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (viii) (0.35 g), 2,4-dichloropyrimidine (0.18 g) and cesium carbonate (0.26 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 4 hours. The mixture was partitioned between water and ethyl acetate, the organic phase washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50-80% ethyl acetate in isohexane.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=4)[C:19]([S:30][CH3:31])=[CH:18]3)=[N:15][CH:16]=2)[CH:6]=1>C1COCC1.O>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[N:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=4)[C:19]([S:30][CH3:31])=[CH:18]3)=[N:13][CH:12]=2)[CH:6]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccn4)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.27 g, 6.4 mmol) was added to an ice-cooled suspension of the methyl ester 269a) (1.0 g, 2.56 mmol) in THF/water (1:1, 50 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum, and the residue was dissolved in water (20 mL) and washed with dichloromethane (2×20 mL). The aqueous phase was acidified with sodium hydrogen sulfate and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. White solid. Yield: 0.9 g (93% of theory)
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)([OH:4])=[O:2]
Reactant: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 66.4 %

Procedure:
A mixture of 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3-dihydropyridazin-6-yl]2-phenylpyrazolo[1,5-a]pyridine (1.94 g) and 24% aqueous sodium hydroxide (2 ml) in methanol (8 ml) was refluxed for 30 minutes and then evaporated in vacuo. The residue was dissolved in water (30 ml) and the aqueous solution was acidified with hydrochloric acid, and extracted with chloroform (25 ml). The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and n-hexane to give 3-[2-(2-carboxyethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.24 g).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@:12]([C:14]2[C:15]([F:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]2([CH2:9][CH2:8][CH2:7]2)[S:5]1(=[O:31])=[O:30])[CH:2]=C.C(=O)(O)[O-:33].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[Br:20][C:18]1[CH:19]=[C:14]([C@@:12]2([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]3([CH2:9][CH2:8][CH2:7]3)[S:5](=[O:31])(=[O:30])[C@@H:4]2[CH2:1][CH2:2][OH:33])[C:15]([F:21])=[N:16][CH:17]=1
Reactant: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C2(CCC2)S1(=O)=O
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)[C@@H](CCO)S(=O)(=O)C12CCC2
Reaction time: 0.08 h
Yield: 101 %

Procedure:
To a solution of tert-butyl ((6R,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.0 g, 3.87 mmol) in DCM (40 mL) and MeOH (10 mL) was added sodium bicarbonate (0.651 g, 7.75 mmol) and the resulting mixture was brought to −78° C. To this mixture was bubbled O3 for 15 min until the starting material was consumed. A stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (0.293 g, 7.75 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach rt and stirred for 30 min. The mixture was carefully quenched with saturated NH4Cl, water was added and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford a white solid as tert-butyl ((6R,7R)-7-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.035 g, 3.91 mmol, 101% yield). LC/MS (ESI+) m/z=541.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 96 h
Yield: 57 %

Procedure:
A solution of 1.0 g (0.0025 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of tetrahydrofuran was treated with 5 ml (0.037 mol) of dipropylamine and stirred at 50° for 96 hrs. All volatiles were removed in a water-jet vacuum and the residue was taken up with ethyl acetate and water. The organic phase was dried over magnesium sulphate, concentrated and the residue remaining was chromatographed over silica gel with methylene chloride/methanol 95:5 as the eluent. After recrystallization from ethyl acetate there was obtained 0.67 g (58%) of (S)-8-chloro-1-(4-dipropylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo-[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 213°-214° and [α]D20 =-68.5° (MeOH, c=0.8%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)=[CH:11][CH:12]=1.[OH-].[Li+]>CO.O1CCCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (+/−)-ethyl 4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoate (46 mg, 0.095 mmol) in methanol (0.19 ml) and tetrahydrofuran (0.095 ml) was treated with aqueous lithium hydroxide (0.095 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.[H-].[Na+]>CN(C=O)C>[C:1]1([C:7]2([C:8]#[N:9])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: BrCCCCBr
Reactant: N#CCC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(C2=CCCCC2)CCCC1

Procedure:
Cyclohex-1-en-1-ylacetonitrile and 1,4-dibromobutane were reacted in DMF at room temperature in the presence of sodium hydride to obtain 1-cyclohex-1-en-1-ylcyclopentanecarbonitrile.
Reaction SMILES: [C:1]1([C:7](=[C:13]([C:15]2[C:16]([Cl:22])=[N:17][N:18]([CH3:21])[C:19]=2[Cl:20])[OH:14])C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.O1CCOCC1>[Cl:22][C:16]1[C:15]([C:13](=[O:14])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([Cl:20])[N:18]([CH3:21])[N:17]=1
Reactant: CCOC(=O)C(=C(O)c1c(Cl)nn(C)c1Cl)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(Cl)c(C(=O)Cc2ccccc2)c1Cl
Temperature: 0 °C
Yield: 59.5 %

Procedure:
17 g (50 mmols) of ethyl 2-phenyl-3-(3,5-dichloro-1-methylpyrazol-4-yl)-3-hydroxyacrylate was dissolved in 50 ml of 6 N HCl and 250 ml of 1,4-dioxane, and heated under reflux for 15 hours. The reaction mixture was poured into 500 ml of ice water, and precipitated crystals were taken out through filtration to obtain 8 g of the intended 1-(3,5-dichloro-1-methylpyrazol-4-yl)-2-phenylethanone as white crystals. m.p.: 94-96° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NCc1ccc(Cl)cc1
Yield: 57.6 %

Procedure:
25 g of 2,5-dichloronitrobenzene and 36.9 g of 4-chlorobenzylamine are heated for two hours at 135° C., it being necessary for the temperature always to be kept below 140° C. After cooling, the mixture is taken up with water and extracted with ethyl acetate. After drying over magnesium sulfate and evaporation under vacuum, the residue is taken up with ether and the crystals obtained are filtered off and washed with ether to give 22.3 g of 2-(4-chlorophenylmethylamino)-5-chloronitrobenzene in the form of crystals melting at 120° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][C:11](=O)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:11]([CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc(Br)cc1NC(=O)CC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(CC2CCCC2)nc2cc(Br)sc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To 5-bromo-3-[(cyclopentylacetyl)amino]thiophene-2-carboxamide (290 mg) were added 2M aqueous sodium hydroxide solution (1.75 mL) and ethanol (3.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL) was added, and the precipitate was collected by filtration to give the title compound (165 mg) as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([N:14]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[CH2:37]1[O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][N:14]([S:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=3[CH3:28])(=[O:17])=[O:16])[C@H:10]([CH:11]([CH3:13])[CH3:12])[C:9]([OH:39])=[O:8])=[CH:31][C:32]=2[O:38]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)O)C(C)C)c(C)c1C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (4.7 g, 8.49 mmol) in a 4:1 mixture of ethanol/tetrahydrofuran (40 mL) was added 10% Pd/C (0.15 g). The reaction mixture was placed under a hydrogen balloon. After 3 h, the reaction mixture was filtered through Celite and the Celite cake was washed with ethanol. The filtrate was concentrated to give of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid (3.9 g) as a white foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([N:22]([CH3:38])[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=3[Cl:37])=[O:24])[CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[Cl:32][C:31]1[C:30]([O:33][CH3:34])=[CH:29][C:28]([O:35][CH3:36])=[C:27]([Cl:37])[C:26]=1[NH:25][C:23](=[O:24])[N:22]([C:18]1[CH:17]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:21]=[CH:20][N:19]=1)[CH3:38]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c1Cl
Agent: [Pd]
Solvent: CO
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(O)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[6-(4-benzyloxy-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-urea (Example 5) (67 mg, 0.121 mmol), palladium on carbon (20 mg), and MeOH (3.5 mL) is stirred for 3 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography to provide the title compound as a brown solid: ESI-MS: 464.2/466.2 [MH]+; tR=3.91 min (purity: 100%, system 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:50])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH2:49][C:33]4([CH2:36][C:35]([C:43]([O:45]C(C)C)=[O:44])([C:37]([O:39]C(C)C)=[O:38])[CH2:34]4)[CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.CO>[C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:50])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH2:49][C:33]4([CH2:36][C:35]([C:43]([OH:45])=[O:44])([C:37]([OH:39])=[O:38])[CH2:34]4)[CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((tert-butoxycarbonyl)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)spiro[3.3]hept-5-ene-2,2-dicarboxylate (15 mg, 0.019 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 4 h. The solvent was removed in vacuo. The crude product was dissolved in dioxane (1 mL) and MeOH (1 mL). H2O was added dropwise, the solid formed was collected by filtration to give desired product in 88% yield. MS: m/e 688.6 (M−H)−, 2.72 min (method 5). 1H NMR (400 MHz, METHANOL-d4) δ 5.88 (s, 1H), 5.57-5.52 (m, 1H), 4.74 (d, J=1.8 Hz, 1H), 4.61 (s, 1H), 2.69 (s, 2H), 2.68-2.48 (m, 4H), 2.33-2.25 (m, 1H), 2.14 (dd, J=17.9, 6.7 Hz, 1H), 1.99-1.83 (m, 2H), 1.77-0.81 (m, 19H), 1.70 (s, 3H), 1.45 (s, 9H), 1.16 (s, 3H), 1.09 (s, 3H), 1.08 (s., 3H), 1.00 (s, 3H), 0.86 (s, 3H).