Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[C:7]([Cl:17])[CH:6]=2.CC(C)([O-])C.[K+]>CN(C=O)C.O>[Cl:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[NH:12][CH:13]([CH3:16])[CH2:14][O:15][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1COc2cnc3cc(Cl)ccc3c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
A solution of 10 g of 3-bromo-7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine in 28 ml of DMF was stirred and to it was added 4.3 g of potassium-t-butoxide. The mixture was stirred at 120°-140° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water and the organics were extracted into dichloromethane. Washing with water, drying over anhydrous magnesium sulfate and evaporation of solvents resulted in a crude solid which was purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. Recrystallization from acetone yielded 2.5 g of solid with a melting point of 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[CH:3]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[OH-].[Na+].[C:30]([O:34][C:35](=[O:41])[C:36](=O)[C:37](=O)[CH3:38])([CH3:33])([CH3:32])[CH3:31]>O.O1CCCC1>[CH3:9][C:7]1([CH3:10])[O:6][C:5]2=[CH:11][C:12]3[N:13]=[C:37]([CH3:38])[C:36]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:41])=[N:1][C:2]=3[CH:3]=[C:4]2[O:8]1
Reactant: CC1(C)Oc2cc(N)c(N)cc2O1
Reactant: CC(=O)C(=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc3c(cc2nc1C(=O)OC(C)(C)C)OC(C)(C)O3

Procedure:
[5,6-diamino-2,2-dimethyl-1,3-benzodioxole; dihydrochloride salt] (U.S. Pat. No. 4,904,775, Example 3D) (6.8 g, 0.02 mmol) was dissolved in a mixture of 25 ml water and 10 ml tetrahydrofuran and the pH of the solution was adjusted to 5.5 by the addition of 2N NaOH. After addition of the compound from Example 1 (3.8 g; 0.02 mol) the mixture was refluxed for 2 hours, concentrated in vacuo to remove the organic solvent tetrahydrofuran and then extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and then evaporated in vacuo to leave an oil which crystallized by the addition of petroleum ether.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:6]1)[CH3:4].Cl[C:22]1[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1.O>CN(C=O)C>[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)=[CH:16][CH:15]=2)=[N:6]1)[CH3:4]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
NaH (60% in oil, 59 mg) was added portionwise at room temperature to a solution of 4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (335 mg) in DMF (3.5 mL). After stirring for 30 min, 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (416 mg) was added, and the mixture was heated for 2 h at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (530 mg).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:14]([O:15][CH2:16][CH2:17][OH:18])=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)([O-])=O.O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:14]([O:15][CH2:16][CH2:17][OH:18])=[N:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(OCCO)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2[nH]nc(OCCO)c2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
Iron powder (0.075 g 1.34 mmol) and ammonium chloride (0.14 g, 2.68 mmol) were added to 2-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (60 mg, 0.27 mmol) in ethanol:water (5 mL, 2:1). The mixture was heated at 85° C. in a sealed vial. After 5 hours, the reaction mixture was filtered and evaporated to afford crude product as a solid. The crude was absorbed on silica gel and chromatographed on a silica gel plug with 10:1 ethyl acetate:methanol. Fractions 2-5 contained 2-(5-amino-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (21.8 mg, 0.112 mmol, 42% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:33].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:33])[CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A stirred mixture of 4-(4-chloro-3-methyl-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.8) (0.59 g, 1.03 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.34 g, 1.13 mmol), tetrakis(triphenylphosphine)palladium (0.071 g, 0.062 mmol) in toluene (8 ml) was heated under reflux conditions for 15 h, heptane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([O:21][CH3:22])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].Cl.[H][H]>CCO.[Pd]>[NH2:18][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 100.4 %

Procedure:
To a solution of 2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g, 177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mL of concentrated HCl. The reaction mixture was hydrogenated using a hydrogen balloon for 22 h. The solution was filtered through celite and concentrated to a minimum volume, after which solid was filtered, washed with ether. The filtrate concentrated again and trituated with EtOH and repeated several times to get out more products. The solid was combined and further dried to give total 50 g of product as light yellow powder (>98%). 1H NMR (400 MHz, DMSO-d6) δ 1.64-2.02 (m, 4H) 2.61 (s, 3H) 2.90 (t, J=11.0 Hz, 2H) 3.24 (m, 2H) 3.72-3.81 (m, 3H) 3.84-4.03 (m, 1H) 5.60 (s, 2H) 6.29-6.50 (m, 1H) 7.01 (d, J=6.8 Hz, 1H) 7.69 (dd, J=7.3, 4.8 Hz, 1H). [M+H] calc'd for C14H20FN3O2, 282. found 282.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 60 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (136 mg) described in Preparation Example 19 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (138 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1([C:41]2[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=2[O:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[CH2:7][CH2:6][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[N:19][CH:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:4][CH2:3]1.[OH-].[K+]>CO.CCOC(C)=O>[OH:1][C:2]1([C:41]2[CH:55]=[CH:54][CH:53]=[CH:52][C:42]=2[O:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:3][CH2:4][N:5]([C:8]([C@:10]2([O:31][C:32]3[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[S:34][CH:33]=3)[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:27])[C:17]3[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:20]=[N:19][CH:18]=3)[C@@H:11]2[CH2:28][CH2:29][CH3:30])=[O:9])[CH2:6][CH2:7]1
Reactant: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2OCCCC(=O)OCC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC[C@H]1N(C(=O)c2cnccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(O)(c2ccccc2OCCCC(=O)O)CC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 86 (40 mg, 0.05 mmol, 1 eq) in MeOH was added KOH (3.5N, 5 equiv). Reaction was brought to 65° C. for 1 hour then cooled down to 23° C. Reaction was diluted with EtOAc, washed with sat. NH4Cl and brine. The organic layer was dried over MgSO4, filtered and concentrated down. HPLC purification, C18, CH3CN/H2O, 70% to 100% CH3CN provided 37 mg (100% yield) of product A91.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])[CH2:3]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[N:45]1C(=O)CC[C:46]1=O>C1COCC1>[CH3:46][NH:45][CH2:3][C:2]([CH3:1])=[CH:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC=C(C)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCC(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene-1-ol (3.2 g, 10 mmol) and triphenylphosphine (2.88 g, 11 mmol) in 20 ml of THF is stirred in an ice bath and 1.78 g (10 mmol) of N-bromosuccinimide is added in small portions over a period of one hour. After addition, the cooling bath is removed and the temperature of the reaction mixture is allowed to rise slowly to room temperature. The mixture is concentrated in vacuo and then diluted with a mixture of ether/petroleum ether. After sitting in refrigerator for several hours, white crystals of triphenylphosphine oxide occur, which is collected by filtration. The filtrate is concentrated and dissolved in 10 ml of dry DMF. To this solution is added 2 g of triethylamine and 0.68 g of methylamine hydrochloride. The resulting mixture is stirred at room temperature for 18 hours and poured into 500 ml of ice-water. The crude product is extracted into ethylacetate and washed with water. After drying over magnesium sulfate, the solvent is removed in vacuo to give the crude product as an oil. This substance is purified on HPLC (2% ethyl acetate in hexane, silica gel column) to give 1-methylamino-2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaene.
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3ccc(F)cc23)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A mixture of 65 parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 270 parts of N,N-dimethylacetamide was hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5 parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)piperidine as a residue (intermediate 21).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Cl)n1
Reactant: CC(C)CN
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(NCC(C)C)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a mixture of 2-chloro-6-methoxypyridine (357 μL, 3 mmol), isobutylamine (596 μL, 6.00 mmol) and Caddick's Catalyst (prepared according to the literature reference Org. Biomol. Chem. 2008, 6, 2820) (35.3 mg, 0.060 mmol) under nitrogen, was added lithium hexamethyldisilazide in tetrahydrofuran (THF) (1 M, 3.750 mL, 3.75 mmol). This was warmed to 70° C. and stirred overnight, then cooled for analysis. The reaction was then further heated by microwaves to 150° C. for 30 minutes. After cooling, purification was attempted by flash silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient), but this failed to provide adequate separation. Purification was then repeated by flash silica (Si) chromatography (0-65% dichloromethane-cyclohexane gradient) to isolate the title compound (37.8 mg). LCMS (2 min, formic) Rt 0.75 min, m/z (ES+) 181 (M+H).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH2:8][C@H:7]1[CH2:6][C@@H:5](O)[CH2:4][CH2:3]2.C(N(S(F)(F)F)CC)C>ClCCl>[CH3:20][C@:14]12[CH2:13][CH2:12][C@H:11]3[C@@H:10]([CH2:9][CH2:8][C@@H:7]4[C@:2]3([CH3:1])[CH2:3][CH:4]=[CH:5][CH2:6]4)[C@@H:15]1[CH2:16][CH2:17][C:18]2=[O:19]
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a solution of epiandrosterone (150 mg, 0.517 mmol) in anhydrous dichloromethane (11 mL) at −78° C. under argon atmosphere was added diethylaminosulfur trifluoride (DAST) (0.082 mL, 0.620 mmol) and the resulting solution stirred for 1 h at −78° C. The solution was then directly evaporated with silica gel and purified by FCC with EtOAc/hexanes (1:99) as eluant to give the desired compound 2 (42 mg, 30%) with a ratio of C2-C3 alkene vs. C3-C4 alkene isomer of less than 90:10. 1H NMR (CDCl3) δ: 0.78 (s, 18-CH3), 0.87 (s, 19-CH3), 0.9-2.0 (residual CH and CH2), 2.06 (m, 16α-CH), 2.44 (dd, J1=8.8 Hz and J2=19.2 Hz, 16β-CH), 5.59 (m, 2-CH and 3-CH). 13C NMR (CDCl3) δ: 11.6, 13.7, 20.2, 21.7, 28.4, 30.2, 30.6, 31.5, 34.7, 35.1, 35.8, 39.7, 41.4, 47.7, 51.4, 54.1, 125.7, 125.8, 221.5. LRMS for C19H29O [M+H]+: 273.1 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[C:4]([F:20])[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[C:25]2[CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[C:25]3[CH3:31])=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1C
Reactant: Cc1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(Cl)cc2F)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
The product from Step 2 (130 mg, 0.437 mmol, 1.00 equiv), 5-amino-3-methyl indazole (64 mg, 0.437 mmol, 1.0 equiv), and EDC (100 mg, 0.524 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.073 mL, 0.524 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) to provide 35 mg (19%) of the title compound as a white solid. MS (ES+) m/e 427 [M+H]+
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.N1C=CN=C1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: ClCCCl
Product: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step B, 400 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (30 mL) was added dropwise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (900 mg [slightly contaminated with imidazole], 1.6 mmol, 1.0 eq.) in 20 mL of anhydrous CH3CN. The reaction was stirred for 16 h at RT then EDC (0.5 g, 2.6 mmol, 1.5 eq.) was added. The resulting mixture was heated to 80° C. for 1 h. The solvent was evaporated and the residue was diluted with CH2Cl2 (25 mL). The solution was washed with H2O (25 mL), NaHCO3 (25 mL, aq.) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-7.5% MeOH/CH2Cl2) to give pure [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=496.2 (M+H)+; MW Calc'd for C24H26N7OS: 495.16.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 2.0 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine, 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of known tert-butyl D-(-)-lactate (292 mg), 4-chlorophenol (197 μl) and triphenylphosphite (343 μl) in dry tetrahydrofuran (16 ml) on an ice bath, diethylazodicarboxylate (315 μl) was added dropwise over about 5 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was evaporated with a rotary evaporator (water bath temperature 25° C.). The residue thus obtained was dissolved in ether (20 ml) and the ethereal solution was washed with water. Ether was evaporated. The residue obtained was then purified by silica gel chromatography [silica gel 55 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2S)-(-)-2-(4'-chlorophenoxy)propionate (330 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[O:4]1)[CH3:2].CCN(CC)CC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:39]([C:33]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=3)(=[O:41])=[O:40])[CH:9]=2)[O:4]1)[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCC1(C)C=Cc2cc(CNc3ccccc3)ccc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(C)C=Cc2cc(CN(c3ccccc3)S(=O)(=O)c3ccc(OC)c(OC)c3)ccc2O1
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of 9 (80 mg, 0.29 mmol) in DCM (3 mL) was added Et3N (0.12 mL, 0.85 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (135 mg, 0.573 mmol). After 24 h, sat. NH4Cl was added to the reaction mixture and the aqueous layer was extracted with DCM (5×2 mL). The organic layers was combined, dried over MgSO4 and concentrated under vacuum. The crude product was purified by column (silica gel, 5:1 Hx/EtOAc) to give a white solid (42.6 mg). Yield: 32%. 1H NMR (CDCl3): δ 7.35 (dd, J=6.4 Hz, 2.0 Hz, 1H), 7.25-7.23 (m, 3H), 7.02-6.98 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.91-6.88 (m, 2H), 4.62 (s, 2H), 3.98 (s, 3H), 3.77 (s, 3H), 1.71-1.65 (m, 2H), 1.43 (s, 3H), 0.94 ppm (t, J=7.6 Hz, 3H). 13C NMR (CDCl3): δ 152.8, 152.5, 148.7, 139.2, 130.5, 129.8, 129.3, 129.2, 128.8, 127.9, 127.8, 126.6, 122.8, 121.4, 121.1, 115.8, 110.4, 79.0, 56.2, 56.1, 54.3, 34.0, 26.0 ppm. MS (ESI) m/z 502 [(M+Na)+]. HPLC: ret. time=5.9 min, 98.9%.