Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([N:10]3[S:18](=[O:20])(=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=13)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[C:4]3[C:9]([N:10]4[S:18](=[O:20])(=[O:19])[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11]=24)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23]1
Reactant: O=S1(=O)c2ccccc2-c2c(CCl)c3ccccc3n21
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2c3n(c4ccccc24)S(=O)(=O)c2ccccc2-3)CC1

Procedure:
Alternatively, 10-Chloromethyl-5-thia-4b-aza-indeno[2,1-a]indene-5,5-dioxide (D37), may be treated with N-methylpiperazine according to the method as described under Description 1, to obtain the above said compound. Melting range (° C.): 121-125; IR spectra (cm−1): 1180, 1289, 1336, 1439; Mass (m/z): 368, 370 (M+H)+; 1H-NMR (ppm): 2.42 (s, 3H), 2.73-2.83 (bs, 8H), 3.88 (s, 2H), 7.22-8.07 (m, 8H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20](O)=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].Cl.C([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][N:25]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([NH2:37])=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 30 min, and then cooled to 0° C. To the mixture was added aqueous ammonium hydroxide solution (10%, 1 mL). The whole was stirred at room temperature for 15 h. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (90 mg, 39%) as pale yellow prisms. MS 489 (MH+). mp 212-213° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1.C[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[C:20]=2[NH2:21])=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:14]=1
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(Cl)cc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3C(F)(F)F)c2N)cc1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (0.500 g, 3.3523 mmol) and 4-chloro-2-(trifluoromethyl)phenylacetonitrile (1.104 g, 5.0284 mmol) in absolute ethanol (15 ml), an ice-cooled solution of sodium methoxide (0.217 g, 4.0228 mmol) in absolute ethanol (8 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜1.25 g of crude material as brownish solid. This material is purified by crystallization from methylene chloride and petroleum ether, to obtain the title compound as brown solid (1.05 g, 83% yield). M.p. 159.2-160.2° C. LC-ESI-HRMS of [M+H]+ shows 369.0712 Da. Calc. 369.072998 Da, dev. −4.9 ppm.
Reaction SMILES: C([O:4][C:5]1[C:14](=[S:15])[C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)C=C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].Cl>[OH:4][C:5]1[C:14](=[S:15])[C:13]2[C:8](=[CH:9][C:10]([CH3:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1
Reactant: C=CCOc1cn(C)c2cc(C)ccc2c1=S
Agent: [Rh]
Agent: Cl
Agent: [Cl-]
Product: Cc1ccc2c(=S)c(O)cn(C)c2c1

Procedure:
Tris(triphenylphosphine)rhodium chloride (0.1 g) was added to the solution of 3-allyloxy-1-methyl-7-methylthio-4-quinolone and the mixture heated under reflux for 2 days. Hydrochloric acid (5M, 20 ml) was added dropwise and the mixture heated under reflux for 2 hours. The solvent was evaporated under reduced pressure at 50° and the resultant residue extracted with aqueous sodium hydroxide (1M, 100 ml). The extract was neutralised with hydrochloric acid (5M, 20 ml) and the solid was collected by filtration. The solid was washed with water (50 ml) and dried to give the novel compound 3-hydroxy-1-methyl-7-methylthio-4quinolone, m.p. 237°.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][NH:5][C:6]([C:8]1[CH:39]=[C:38]2[C:11]([CH2:12][C:13]3[C:17]([C:18](=[O:31])[CH:19]([C:29]#[N:30])[C:20](=[O:28])[NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:16][N:15]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:14]=32)=[CH:10][CH:9]=1)=[O:7].Cl>[OH-].[K+].C(O)C>[C:32]1([N:15]2[C:14]3[C:38]4[C:11]([CH2:12][C:13]=3[C:17]([C:18](=[O:31])[CH:19]([C:29]#[N:30])[C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16]2)=[CH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:40])=[O:2])=[O:7])[CH:39]=4)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)CNC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(C(=O)NCC(=O)O)cc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
N-[1,4-Dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl) -indeno[1,2-c]pyrazol-7-yl]carbonyl-glycine methyl ester (0.84 g) is suspended in 1% KOH solution in 95% ethanol (22.3 ml) and heated under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture is acidified to pH 2 with 23% HCl and then diluted with ice water. The precipitate is filtered, washed with water and then crystallized from CH2Cl2 /ethanol to yield 0.65 g of pure N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl) -indeno[1,2-c]pyrazol-7-yl]carbonyl glycine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:28][S:29]([C:32]2[C:33]3[CH:34]=[CH:35][N:36]=[CH:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O:45][CH2:46][CH2:47]O)(=[O:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:42]([O:45][CH2:46][CH2:47][N:28]([CH:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1)[S:29]([C:32]1[C:33]2[CH:34]=[CH:35][N:36]=[CH:37][C:38]=2[CH:39]=[CH:40][CH:41]=1)(=[O:31])=[O:30])(=[O:44])[CH3:43]
Reactant: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)NS(=O)(=O)c2cccc3cnccc23)cc1
Reactant: CC(=O)OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)N(CCOC(C)=O)S(=O)(=O)c2cccc3cnccc23)cc1
Yield: 52.2 %

Procedure:
1.0 g of the product obtained in Example 73 was dissolved in 5 ml of tetrahydrofuran, to the solution were added 220 mg of ethylene glycol monoacetate and 685 mg of triphenylphosphine in place of N-tert-butoxycarbonylethanolamine, according to the procedure described :n Example 136, to obtain 600 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](I)=[C:13]([C:16]#[N:17])[C:12]([CH3:18])=[N:11]1.[Li]CCCC.CON(C)[C:27](=[O:36])[CH:28]([CH3:35])[CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32]>CCOCC>[CH3:32][O:31][CH:30]([O:33][CH3:34])[CH2:29][CH:28]([CH3:35])[C:27]([C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:11]=[C:12]([CH3:18])[C:13]=1[C:16]#[N:17])=[O:36]
Reactant: COC(CC(C)C(=O)N(C)OC)OC
Reactant: COc1ccc(-n2nc(C)c(C#N)c2I)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(-n2nc(C)c(C#N)c2C(=O)C(C)CC(OC)OC)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To 1-(2-fluoro-4-methoxyphenyl)-5-iodo-3-methyl-1H-pyrazole-4-carbonitrile (66 mg, 0.18 mmol) in Et2O (1.5 mL) at −78° C. was added n-BuLi (2.5 M solution in hexane, 0.1 mL, 0.24 mmol). After stirring for 15 min, N,4,4-trimethoxy-N,2-dimethylbutanamide was added in Et2O (1.5 mL). The reaction was stirred at −78° C. for 15 hours while warming to −40° C. The reaction was quenched with water and extracted using a mixture of Et2O and DCM. Drying using a phase separator followed by concentration and purification using silica gel (heptane-EtOAc, 1:0 to 0:1) afforded 5-(4,4-dimethoxy-2-methylbutanoyl)-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (33 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[C:5](Br)[C:3]=1[NH2:4].BrC1C=C(C=C(Br)C=1OC)N.BrBr>C(Cl)Cl>[Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[CH:5][C:3]=1[NH2:4]
Reactant: COc1c(Br)c(Br)c(N)c(Br)c1Br
Agent: BrBr
Agent: COc1c(Br)cc(N)cc1Br
Solvent: ClCCl
Product: COc1c(Br)cc(N)c(Br)c1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:18])[C:5]([Cl:17])=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[CH:19](B1OC(C)(C)C(C)(C)O1)=[CH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)CC.CN(C=O)C>[Cl:17][C:5]1[C:4]([Cl:18])=[CH:3][C:2]([CH:19]=[CH2:20])=[CH:7][C:6]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc(Cl)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCO
Solvent: O
Product: C=Cc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 90 °C

Procedure:
{[(5-Bromo-2,3-dichlorophenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane (1 eq.) from the previous step and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.) were combined in a 2:1 (v/v) mixture of DMF:n-PrOH (0.11 M). To this solution was then added palladium(II) acetate (0.05 eq.) and triphenylphosphine (0.15 eq.) before the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 N aq. Na2CO3 (2 eq.) was added and the resulting biphasic suspension was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a black oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6]([NH:9][CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])=[CH:7][CH:8]=1.N[C:20](N)=[O:21].O>ClC(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[C:20](=[O:21])[NH:18][C:5]=2[CH:4]=1
Reactant: CC(Nc1ccc(Cl)cc1N)c1cccnc1
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(c1cccnc1)n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 190 °C
Yield: 63.5 %

Procedure:
A mixture of 41.5 parts of 4-chloro-N1 -[1-(3-pyridinyl)ethyl]-1,2-benzenediamine monohydrochloride and 27 parts of urea is stirred and heated for 1.50 hours in an oil-bath at about 190° C. The reaction mixture is cooled, water and trichloromethane are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 26 parts (63.5%) of 5-chloro-1,3-dihydro-1-[1-(3-pyridinyl)ethyl]-2H-benzimidazol-2-one; mp. 190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1ccc(Cl)c([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 1.85 g of 4-chloro-3-nitrobenzaldehyde and 1.5 g of 2,4-pentanedione. Yield 1.32 g, mp 110°-111° C.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>C(O)C>[C:1]([N:5]1[C:17]([NH2:18])=[C:14]([C:15]#[N:16])[CH:13]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)(C)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1ncc(C#N)c1N
Yield: 87.5 %

Procedure:
To a mixture of tert-butylhydrazine (40 g, 0.32 mol), sodium methoxide (18 g, 0.32 mol) and ethanol 150 ml) was added ethoxymethylene malononitrile (42 g, 0.32 mol). The reaction mixture was heated to reflux for 2 hours and the solvent was removed in vacuo. The residue was extracted with chloroform, washed with water and the organic layer was concentrated in vacuo to afford 46 g (87%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile as a semi-solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:50])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1>[O:50]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 40.8 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-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)benzoate (500 mg, 0.709 mmol) and aqueous sodium hydroxide 10N (1.42 mL, 14.2 mmol) in dioxane (10 mL) was heated at 78° C. for 3 h. The reaction was filtered and the resulting clear solution was purified by prep HPLC to provide the title compound as white solid (200 mg, 39%). LCMS: m/e 691.59 (M+H)+, 2.53 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.45-5.34 (m, 1H), 4.85 (s, 1H), 4.74 (s, 1H), 3.55-3.40 (m, 1H), 3.39-3.22 (m, 6H), 3.22-3.11 (m, 4H), 3.11-3.03 (m, 1H), 3.04-2.94 (m, 1H), 2.36-1.18 (m, 22H), 1.76 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:40]1[C:48]2[N:47]=N[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:14]2[C:13](=[CH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:45][C:44]3[CH:43]=[CH:42][CH:41]=[CH:40][C:48]=3[NH2:47])=[O:26])=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
6-(2-(9H-thioxanthen-9-ylidene)acetamido)hexanoic acid (367 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (302 mg, 66% yield) as a brown solid. LC-MS (m/z) 458 (M+1).
Reaction SMILES: C[S-].[Na+].C[S:5][C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[C:21]([S:26]C)=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:14]=2)=[CH:10][CH:9]=[CH:8][N:7]=1>Cl>[C:15]1([NH:19][C:20]2[C:21]([SH:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:11]2[C:6]([SH:5])=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: CSc1ncccc1Nc1cccc(Nc2cccnc2SC)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Product: Sc1ncccc1Nc1cccc(Nc2cccnc2S)c1
Temperature: 100 °C

Procedure:
A 250 mL round bottom flask is charged with sodium methanethiolate (5.18 g, 73.8 mmol), N1,N3-bis(2-(methylthio)pyridine-3-yl)benzene-1,3-diamine (13.25 g, 61.5 mmol) and Hexamethyl phosphoramide(HMPA) (100 mL). The reaction mixture is heated up to 100° C. for 7 h. The reaction is cooled to room temperature, and 100 mL of 1N HCl is added. The reaction mixture is extracted with 3×100 mL ethyl acetate. The organic portion is washed with 3×50 mL Brien, dried over sodium sulfate and evaporated to yield the desired compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCCC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: ClCCCCn1ccc2ccccc21
Product: CCCC(=O)Nc1ccc(C2CCN(CCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(4-chlorobutyl)-1H-indole and N-[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 418.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].Cl>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][CH:3]=1)=[O:34]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3ccc(N)cc3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0 g, 3.23 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (488 mg, 3.23 mmol). The mixture was stirred at room temperature for one hour and poured into 200 ml of 0.02M HCl solution with vigorous stirring. The resulting precipitates were filtered, washed with water, and dried in vacuo to give methyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 1.38 g, 93%.
Reaction SMILES: F[CH:2](F)[C:3]1[CH:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:5]([CH3:17])[N:4]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:26]>>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([O:8][C:6]2[N:5]([CH3:17])[N:4]=[C:3]([CH:2]=[O:26])[CH:7]=2)[N:10]=[N:11][CH:12]=1
Reactant: O
Reactant: COc1cnnc(Oc2cc(C(F)F)nn2C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cnnc(Oc2cc(C=O)nn2C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
3-[[3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl]oxy]-5-methoxypyridazine (Compound No. 45, 4.5 g, 0.017 mole) and dichloromethane (80 mL) were stirred and cooled with a water bath while aluminum chloride (4.3 g, 0.031 mole, (note: this aluminum chloride was old and wet) was added and the mixture was then stirred at room temperature for 5 hours. The mixture was poured into cold water and the aqueous phase washed three times with dichloromethane. The pH of the aqueous phase was adjusted to 4, using 10% sodium hydroxide; and the product was extracted with ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 5-[(5-methoxy-3-pyridazinyl)oxy]-1-methyl-1H-pyrazole-3-carboxaldehyde (0.50 g, 12% yield) as white solid.