Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH:4]=[CH:5][Cl:6].[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[C:8]([C:9](=[C:3]([CH2:2][Cl:1])/[CH:4]=[CH:5]/[Cl:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=CCl)CCl
Product: CCOC(=O)C(C(=O)OCC)=C(/C=C/Cl)CCl
Yield: 76.9 %

Procedure:
1,4-Dichloro-3-buten-2-one (0.0556 kg, 0.4 mole) and diethyl malonate (0.064 kg, 0.4 mole) were condensed under identical conditions to those described in Example 1(b) to give the title compound 0.0865 kg (77%; purity, g.l.c., 87.85%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>C(#N)C>[C:18]([O:21][CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.62 g, 5.17 mmol, from Step A) was dissolved in acetonitrile (15 mL) and sodium acetate (2.8 g, 34 mmol) was added. The mixture was heated to 80° C. for 4 hours, then allowed to stand at room temperature overnight. Acetonitrile was removed in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with two further portions of ethyl acetate. The combined extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-60% EtOAc/hexanes afforded purified product (0.95 g, 63%). H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 5.36 (s, 2H), 4.53 (q, 2H), 2.25 (s, 3H), 1.46 (t, 3H); LCMS (M+H)+: 293.0.
Reaction SMILES: C(O[C:4](=[O:8])[C:5]#[C:6][CH3:7])C.[CH3:9][CH:10]([NH:18][NH2:19])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1>C(O)CCC>[CH3:7][C:6]1[NH:19][N:18]([CH:10]([CH3:9])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:8])[CH:5]=1
Reactant: CC#CC(=O)OCC
Reactant: CC(NN)c1ccc(F)cc1
Solvent: CCCCO
Product: Cc1cc(=O)n(C(C)c2ccc(F)cc2)[nH]1

Procedure:
8.3 g (0.074 mol) of tetrolic acid ethyl ester and 11.3 g of α-methyl-4-fluorobenzylhydrazine in 70 ml of n-butanol were heated for 8 hours under reflux.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][C:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25]3)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:5]=1)#[N:2].C(=O)([O-])[O-:36].[K+].[K+].OO>CS(C)=O.CCOC(C)=O.O>[NH2:2][C:1](=[O:36])[CH2:3][C:4]1[S:8][C:7]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]3([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:25][CH2:26][CH2:27]3)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CC#N)s2)nn1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CC(N)=O)s2)nn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 47.8 %

Procedure:
To a solution of t-butyl 6-(5-(cyanomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (12.5 g, 26.0 mmol) in DMSO (260 mL) was added potassium carbonate (14.4 g, 104.1 mmol). The mixture was cooled to 0° C. and hydrogen peroxide (86 mL) was slowly added. The reaction was warmed to rt and stirred for 90 min. The reaction was diluted with EtOAc (200 mL) and water (500 mL), and the organic layer was washed three times with brine (150 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (CH3CN/CH2Cl2) to afford 6.2 g of t-butyl 6-(5-(2-amino-2-oxoethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a reddish solid. This compound was combined with other batches (15.5 g overall), dissolved in 25% TFA/CH2Cl2, and stirred for 1 h. The reaction was then concentrated, dissolved in ethyl acetate (75 mL), and washed three times with potassium carbonate. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was recrystallized with THF to give 10.8 g of 1-(2-((-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyrimidin-5-yl)-1H-pyrrole-3-carboxamide as an off-white solid (M+H=399.1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:19]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:19])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1

Procedure:
trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00 g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrous DMF (360 mL) were stirred at 60° C. under N2 for 6 h. The reaction was diluted with DCM (˜600 mL), washed with water and brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude material was purified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCM to 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid; By 1H NMR analysis, the product was contaminated with 0.35 eq. of NIS-impurity. The product was carried onto the next reaction without further purification; MS (ES+): m/z 391.92 (100) [MH+], 393.88 (50) [MH+2], 394.89 (10) [MH+3]; tR (polar-5 min/openlynx) 2.79 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.C[C:17](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:18]>C(O)=O>[CH:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhyddride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-isopropoxyiminoacetic acid (syn isomer, 3.75 g.), mp. 168° to 169° C. (dec.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[CH:24][N:23]=2)=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].O>ClCCl>[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[C:24]([Br:1])[N:23]=2)=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Yield: 85.7 %

Procedure:
0.42 g (2.4 mmol) of N-bromosuccinimide is added, under a nitrogen atmosphere at ambient temperature, to a solution of 0.67 g (2.4 mmol) of methyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of dichloromethane. After stirring for 2 h 30, water is added. The precipitate formed is filtered off, rinsed with water, and dried overnight at 40° C. under reduced pressure. 0.77 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[CH2:12]([N:15]([CH2:35][CH2:36][CH3:37])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3F)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[CH2:13][CH3:14].[Cl-].[NH4+]>C1COCC1>[CH2:35]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([C:26](=[O:34])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[CH2:36][CH3:37]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)c3ccccc3F)c2C1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(C(=O)c3ccccc3ON=C(C)C)c2C1
Yield: 142 %

Procedure:
To 47.5 mg of acetone oxime (0.65 mmol) in 25 ml of THF were added 73 mg (0.65 mmol) of potassium t-butoxide. The mixture was stirred at room temperature for one hour after which 210 mg of 2-di-n-propylamino-8-(2'-fluorobenzoyl)-1,2,3,4-tetrahydronaphthalene in THF were added via a syringe. The resulting mixture was refluxed for three hours after which it was cooled and poured into an aqueous solution of ammonium chloride. The mixture then was extracted with either, and the extract was dried and concentrated to obtain 343 mg of 2-di-n-propylamino-8-[2[(isopropylideneamino)oxy]benzoyl]-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=[O:14])=O)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH:23]1([C:17]2[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[N:18]=2)[C:13]([NH:12][NH2:11])=[O:14])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cc(C(=O)NNC(=O)OCc2ccccc2)cc(C2CCCC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)NN)cc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 90.5 %

Procedure:
Pd/C (500 mg, 10% Pd) is added to a solution of N′-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g, 7.42 mmol) in THF (50 mL) and methanol (50 mL). The mixture is stirred at rt under 1 bar of H2 for 25 h. The catalyst is removed by filtration and the filtrate is concentrated and dried under HV to give the title compound (1.58 g) as an off-white solid; LC-MS**: tR=0.51 min, [M+1]+=236.20; 1H NMR (D6-DMSO): δ 1.60-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.08-3.19 (m, 1H), 3.86 (s, 3H), 4.56 (s br, 2H), 6.93 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18](Cl)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCc2cc(Cl)nnc2C1)N1CCN(C2CCC2)CC1
Reactant: C1COCCN1
Product: O=C(CN1CCc2cc(N3CCOCC3)nnc2C1)N1CCN(C2CCC2)CC1

Procedure:
A solution of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine (0.2 g) in morpholine (5 ml) is heated at 200° C. in a microwave for 2 hr. The excess morpholine is removed in vacuo. The crude mixture is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.60 (1H, s), 3.86 (2H, s), 3.82 (4H, t), 3.50-3.70 (8H, m), 3.40 (2H, s), 2.62-2.84 (5H, m), 2.24-2.32 (4H, m), 1.60-2.06 (6H, m); MS (+VE) m/z 401.2 (M++1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:10])[NH2:9])[CH:3]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2cccnc2)ns1
Temperature: 25 °C
Yield: 4.4 %

Procedure:
To a solution of pyridine-3-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 110 mg (4.38%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ncccc2N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a stirring solution of 1-methyl-4-(3-nitro-pyridin-2-yl)-piperazine (LXXXIII) (1.30 g, 5.85 mmol) in MeOH (15 mL) was added 10% Pd/C. The solution was purged with hydrogen. The solution was stirred at room temperature for 16 h under hydrogen. The solution was filtered through a pad of Celite and concentrated to a residue under vacuum. The residue was purified by column chromatography (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to afford 2-(4-methylpiperazin-1-yl)pyridin-3-amine (LXXXIV) (0.466 g, 2.42 mmol, 52% yield) as a tan solid. ESIMS found for C10H16N4 m/z 192.4 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])=[N:6][CH:7]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:34])([F:33])[F:21])=[CH:24][CH:25]=2)=[CH:7][N:6]=1)=[NH:10]
Reactant: COc1ccccc1CNC(=N)Nc1ccc(I)cn1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1CNC(=N)Nc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 120 °C
Yield: 26.1 %

Procedure:
The preparation was carried out analogously to Example 86, using 0.128 g (0.316 mmol) N-(5-iodopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.097 g (0.511 mmol) [4-(trifluoromethyl)phenyl]boric acid, 0.112 g (1.052 mmol) sodium carbonate, and 0.022 g (0.019 mmol) tetrakis-(triphenylphosphine) palladium(0). The mixture was likewise heated for 60 min at 120° C. in a CEM microwave (230 watts). After filtration and purification via preparative HPLC, 33 mg N-(2-methoxybenzyl)-N′-{5-[4-(trifluoromethyl)phenyl]pyridin-2-yl}guanidine was isolated, a portion of which was present in the form of the acetate salt (base/acetate in a ratio of 1:0.6).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH:59]([CH3:61])[CH3:60])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH:59]([CH3:60])[CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:66])[CH3:67])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 69.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethyl-siloxy)-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos18-ene-2,3,10,16-tetraone (130 mg) in acetonitrile (4 ml) was added a solution of 2% HF in aqueous acetonitrile (70 μl), and the mixture stirred at room temperature. After 5.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (80 mg).
Reaction SMILES: [CH:1](/[C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20]C)=[CH:10][CH:11]=1)[CH2:6]2)=[CH:2]\[CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH:1](/[C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)=[CH:2]\[CH2:3][CH3:4]
Reactant: CC/C=C/C12CCC(=O)C(C)=C1c1ccc(OC)cc1C2
Agent: Cl
Solvent: c1ccncc1
Product: CC/C=C/C12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 190 °C

Procedure:
A mixture of 9a-[(1E)-1-butenyl]-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (31.7 mg, 0.112 mmol) and pyridine hydrochloride (384 mg, 3.32 mmol) was placed under a nitrogen atmosphere and heated in an oil bath at 190° C. for 65 minutes. After cooling to room temperature, the reaction mixture was partitioned between water (4 ml) and EtOAc (10 mL). The organic phase was recovered, washed with brine (5 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (30 mg). The crude product was purified by silica gel chromatography on a Biotage FLASH 12S column (1.2×7.5 cm), eluting with 3:1 hexanes-EtOAc. The product containing fractions were concentrated under vacuum and the residue lyophilized from benzene to provide 9a-[(1E)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a yellow, amorphous solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][N:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([CH:28]=CN(C)C)=[N:15]2)=[O:10]>C1COCC1>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][N:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([CH:28]=[O:2])=[N:15]2)=[O:10]
Reactant: COC(=O)c1ccn2nc(C=CN(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn2nc(C=O)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Sodium periodate (0.52 g, 2.4 mmol) was added to pH 7 buffer solution (2.5 ml) of 3-benzyl-2-(2-dimethylamino-vinyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.17 g, 0.48 mmol) in THF (3.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc (30 mL). The filtrate was washed with saturated NaCl (2×30 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the titled compound as a solid (0.15 g, 100%): 1H NMR (CDCl3) δ 9.41 (s, 1H), 7.16–7.40 (m, 7H), 5.68 (s, 2H), 3.88 (s, 3H); MS (ESI+) 312 (M++H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:39]=[CH:40]/[CH2:41][C:42]([O:45][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])([CH3:44])[CH3:43].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29]/[CH:39]=[CH:40]/[CH2:41][C:42]([O:45][Si:46]([CH2:47][CH3:48])([CH2:49][CH3:50])[CH2:51][CH3:52])([CH3:43])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 100 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (400 mg, 0.734 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (431 mg, 1.47 mmol), sodium hydride (60% in oil, 88 mg, 2.20 mmol), 15-crown-5 (162 mg, 0.735 mmol) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (at room temperature for 2 hours), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (556 mg, 100%) as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[SH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Sc1ccccn1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A suspension of 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (297 mg), potassium carbonate (171 mg) and 2-mercaptopyridine (129 mg) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as a pale-yellow solid (yield 281 mg, yield 85%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:18](=O)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:11]2)(=[O:6])=[O:5].[CH3:28]I.[ClH:30]>CN(C)C=O>[ClH:30].[CH3:28][N:7]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:11]2)[S:4]([CH3:3])(=[O:6])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)CCN(CCCc1ccccc1)C2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.17 g) in dimethylformamide (10 mL) at 0 C is added a solution of Example 22 (1.0 g) in dry dimethylformamide (10 mL). After stirring for 30 minutes, the reaction is treated with methyl iodide (0.5 mL), warmed to room temperature and allowed to stir for 12 hours. The reaction mixture is poured into cold 10% HCl and the product extracted out with CH2Cl2. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated. Using the procedure outlined in Example 2, the resulting residue can be reduced to provide after chromatography on silica gel and salt formation the desired product.