Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][CH2:14][C@@H:15]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[CH:25][C:20]=2[C:19](I)=[CH:18]1)[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:27]1([C:33](=[N:40][C:41]2[CH:42]=[N:43][CH:44]=[C:45]([CH:52]=2)[C:46](N(OC)C)=[O:47])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[Si:6]([O:13][CH2:14][C@@H:15]([N:17]1[C:21]2[N:22]=[CH:23][N:24]=[CH:25][C:20]=2[C:19]([C:46]([C:45]2[CH:44]=[N:43][CH:42]=[C:41]([N:40]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:52]=2)=[O:47])=[CH:18]1)[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl magnesium chloride (68.8 mL, 138 mmol, 2.0 M in THF) was added to 7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (52.2 g, 125 mmol) (see Preparation 14) in THF (400 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (47.5 g, 138 mmol) (see Preparation 23) in THF (100 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (2×250 mL).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1([C:27]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[CH:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCCC3)c2)n1
Temperature: 200 °C

Procedure:
3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (193 mg, 0.80 mmol), bromotris(triphenylphosphine)copper (186 mg, 0.2 mmol) and caesium carbonate (230 mg, 0.70 mmol) were dissolved/suspended in DMA (3.5 mL). The reaction mixture was heated for 40 mins at 200° C. in a microwave reactor then allowed to cool, filtered and reduced in vacuo. The crude product was purified by chromatography on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound as a slightly yellow foam (176 mg). 1H NMR δ (d6-DMSO): 1.61 (m, 2H), 1.73 (m, 4H), 1.94 (m, 2H), 2.28 (m, 2H), 3.78 (s, 3H), 4.08 (t, 2H), 4.59 (t, 2H), 4.95 (m, 1H), 6.56 (d, 1H), 6.88 (t, 1H), 7.28 (m, 1H), 7.43 (t, 1H), 7.56 (m, 1H), 7.59 (d, 1H), 7.99 (d, 1H), 8.41 (m, 1H), 10.85 (s, 1H); m/z 462 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc([N+](=O)[O-])c4)ccc31)C1CCC(C2)N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(N)c4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a solution of the product of step A (48 mg, 0.09 mmol) in EtOH (2 mL) and water (1 mL) was added iron powder (27 mg, 0.48 mmol) and ammonium chloride (5.7 mg, 0.10 mmol). The mixture was heated at reflux for 3 h, cooled to ambient temperature and filtered through a celite bed. The filtrate was extracted with chloroform and the organic layer dried over sodium sulfate then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (28 mg, 62%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.17-7.23 (m, 2H), 6.74 (dd, J=7.3, 1.2 Hz, 1H), 5.17-5.36 (m, 1H), 4.57-4.88 (m, 1H), 3.85 (s, 2H), 3.60 (s, 3H), 3.28-3.40 (m, 1H), 2.48 (d, J=16.5 Hz, 1H), 2.17-2.33 (m, 2H), 1.91-1.97 (m, 1H), 1.54-1.65 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [Cl-].[P:2]([O-:10])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])=[S:3].O[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[P:2]([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])([O:10][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)=[S:3]
Reactant: On1cccn1
Reactant: CCOP([O-])(=S)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=S)(OCC)On1cccn1
Reaction time: 12 h
Yield: 91 %

Procedure:
112 of diethyl thiophosphate chloride were added to 55 parts of 1-hydroxypyrazole and 50 parts of sodium carbonate in 600 parts of acetonitrile at 25° C., with stirring. Stirring was continued for another 12 hours. The solid product was filtered off with suction and washed with two portions of 50 parts of acetonitrile. The filtrate was concentrated in a rotary evaporator at from 20° to 40° C. under 20 mbar. The residue was dissolved in 300 parts by weight of methylene chloride, the organic phase was extracted with three portions of 50 parts by weight of saturated aqueous NaHCO3 solution, the methylene chloride solution was dried with magnesium sulfate and the solvent was stripped off in a rotary evaporator at from 20° to 40° C. under 20 mbar to give 127.5 parts by weight (91% of theory) of O-pyrazol-1-yl O,O-diethyl thiophosphate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)s1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)thiophene-2-carbonitrile (1.3 g, 5.0 mmol) that was obtained in Example 4 (4a) and a 40% aqueous solution of hydroxylamine (0.7 ml). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane to afford the title compound (1.2 g) in a yield of 81% as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH3:17])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:17])[S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1
Reactant: CNCc1ccc(OCc2ccc(OC)cc2)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of intermediate 33 (2.7 g, 8.0 mmol, 1 eq) in DCM (10 mL) was added 4-fluorobenzene-1-sulfonyl chloride (1.9 g, 9.6 mmol, 1.2 eq) and DIEA (2.8 mL, 16.0 mmol, 2 eq). After stirring at room temperature for 1 h, the reaction was washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-40% EtOAc/hexane) to give 2.48 g (63%) of N-(4-(4-methoxybenzyloxy)-3-bromobenzyl)-4-fluoro-N-methylbenzenesulfonamide (34).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:39](O)[CH2:40][OH:41].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:41][CH2:40][CH2:39][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CC(=O)OCCCCCCCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
7.85 g of 3-acetoxy-7α-(11-acetoxyundecyl)-1,3,5(10)-estratrien-17-one is stirred under reflux in 51 ml of dichloromethane and 51 ml of ethylene glycol with 24 ml of trimethyl orthoformate and 159 mg of p-toluenesulfonic acid for 0.5 hour. For working up purposes, the mixture is diluted with dichloromethane, washed with sodium bicarbonate and sodium chloride solutions, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 6.5 g of pure 3-acetoxy-7α-(11-acetoxyundecyl)-17,17-ethylenedioxy-1,3,5(10)-estratriene, [α]D =13.4°, as an oil.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].[CH:28](=[C:35]1[C:43]2[C:42](Cl)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:28](=[C:35]1[C:43]2[C:42]([N:25]3[CH2:24][CH2:23][CH:22]([C:14]4[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[C:12]([C:7]5[CH:8]=[CH:9][C:10]([F:11])=[C:5]([Cl:4])[CH:6]=5)[N:13]=4)[CH2:27][CH2:26]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccccc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccccc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 5-benzylidene-4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.33 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL 0.0098 mol; 7.6 equiv); 2-propanol (10 mL) and microwave at 100° C. for 30 min. Cool and concentrate in vacuo. Dilute with saturated sodium bicarbonate solution and extract with DCM. Wash organic layer with water and brine and dry over anhydrous sodium sulfate. Concentrate the crude compound and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.09 g; 12.2%). MS (ES+): m/z=572 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[I:10]N1C(=O)CCC1=O.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([I:10])=[C:4]([CH:3]=1)[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(N)cc1Br
Agent: F[B-](F)(F)F
Agent: [IH2+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(I)c(N)cc1Br
Yield: 83.6 %

Procedure:
A solution of 3-bromo-4-methylaniline (5.00 g, 26.9 mmol), N-iodosuccinimide (4.53 g, 20.2 mmol) and bis(pyridine)iodonium tetrafluoroborate (2.70 g, 7.26 mmol) in DCM (100 mL) was stirred at room temperature overnight. The mixture was diluted with DCM, washed sequentially with saturated aqueous NaHSO3 and water, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2% and 3%), to provide 5-bromo-2-iodo-4-methylaniline as a yellow solid (5.27 g, 63% yield). Mass spectrum m/z 312, 314 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=0.6 Hz, 1H), 6.94 (s, 1H), 4.17-3.91 (br.s, 2H), and 2.25 (s, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O)=[C:30]([CH3:40])[CH:29]=1.Cl.[CH3:43][C:44]([CH3:54])([CH3:53])[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][C:44]([CH3:54])([CH3:53])[CH3:43])[CH2:48][CH2:49]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: COC(=O)c1ccc(CCCC(=O)O)c(C)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
HBTU (910 mg, 2.4 mmol) was added to a solution of 4-(3-carboxy-propyl)-3-methyl-benzoic acid methyl ester from Example E30 (378 mg, 1.6 mmol) and 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (467 mg, 1.9 mmol) in dichloromethane (15 ml) and DIEA (0.836 ml, 4.8 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane) to yield the title compound (582 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:37])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[CH2:30][N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:38](OCC)=[O:39])=[N:10]2)=[CH:5][CH:4]=1.[NH4+:43].[OH-]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:37])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[CH2:30][N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:38]([NH2:43])=[O:39])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3CN(C)C(=O)NC)cc1)C2=O
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)N(C)Cc1ccccc1-c1ccc(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 48 %

Procedure:
Ethyl 1-(4-methoxyphenyl)-6-[2′-({methyl[(methylamino)carbonyl]amino}methyl)-1,1′-biphenyl-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (130 mg, 0.2 mmol) was dissolved in 7.5 mL of 1,4-dioxane. Concentrated NH4OH (7.5 mL) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 4 days. The mixture was stripped and chromatographed using 3% MeOH:CHCl3 with 0.1% concentrated NH4OH. The fractions containing desired product were combined and purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 71 mg of desired product (48% yield). MS (ES+): 539.4, (M+H)+. 1HNMR (CDCl3) δ 7.48 (t, 2H), 7.39-7.19 (m, 9H), 6.95 (m, 3H), 6.00 (bs, 1H), 4.47 (s, 2H), 4.189 (t, 2H), 3.83 (s, 3H), 3.41 (t, 2H), 2.77 (s, 3H), 2.72 (s, 3H) ppm.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Cl:19].CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[CH:18]=[C:17]([CH:23]=[O:24])[S:16][C:15]=1[Cl:19]
Reactant: CN(C)C=O
Reactant: Clc1sccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
n-BuLi (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0° C. After 15 min, the mixture is cooled to −70° C. A solution of 3-bromo-2-chlorothiophene (49.4 g) in THF (20 mL) is added maintaining the internal temperature <−65° C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at −70° C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1) and the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g (54%) of the title compound as a light yellow solid. Physical characteristics: M.p. 61-62° C.; 1H NMR (300 MHz, DMSO-d6) δ9.82, 8.14; 13C NMR (100 MHz, CDCl3) δ181.6, 140.9, 138.5, 138.1, 112.8.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH:21]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1)=[O:22]
Reactant: c1ccc(-c2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 75 mL of dimethylformamide was cooled to 0° C., and 15 mL of phosphorus oxychloride was added with stirring. The solution was allowed to warm to room temperature, and then a solution of 20.4 grams (0.127 mole) of 2-phenylthiophene in 20 mL of dimethylformamide was added in one portion. The reaction mixture was heated to 80° C. where it stirred for 24 hours. It was then poured into 250 mL of an aqueous, 10% sodium hydroxide solution containing 50 grams of ice. The resulting slurry was extracted with chloroform, and the extract was washed in succession with an aqueous solution saturated with sodium chloride and water. The organic phase was dried over anhydrous magnesium sulfate and filtered. TThe filtrate was concentrated under reduced pressure to a brown residue. Purification of this residue by column chromatography on silica gel, eluting with ethyl acetate:n-hexane (15:85) yielded 18.0 grams of 2-formyl-5-phenylthiophene.
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:42]([O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])=[O:43]>O1CCCC1>[O:24]=[C:4]1[N:3]=[C:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]([Cl:49])([Cl:48])[Cl:47])[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]1=3
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: O=C(Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1)OCC(Cl)(Cl)Cl

Procedure:
A 500 mg amount of 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended and stirred in 25.0 ml of dry tetrahydrofuran, then 320 mg of [1,8-bis(dimethylamino)naphthalene,N,N, N',N'-tetramethyl-1,8-naphthalenediamine] (Proton Sponge®) was added followed by 0.207 ml of 2,2,2-trichloroethyl chloroformate. This mixture was heated at reflux for 16 hours. The reaction mixture was quenched by pouring it into 200 ml of water and the precipitate formed was collected by filtration to give 419 mg of the desired product as a white solid, m.p. 225°-226° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4](O)=[O:5].[NH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13]>>[NH2:15][N:14]1[C:4](=[O:5])[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[N:10][N:11]=[C:12]1[SH:13]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: NNC(=S)NN
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
which is formed in step (1) and which was hitherto unknown, is reacted, in a second stage, either directly in the solution obtained or after intermediate isolation and if appropriate after prior saponification to give free trimethylpyruvic acid (VI), with thiocarbohydrazide (H2N--NH--CS--NH--NH2) in an aqueous solution containing a hydrogen halide acid, at a temperature from about 20° to 100° C. in a manner which is in itself known to give 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VII), and this compound is alkylated in alkaline solution, in a third stage, by means of methyl iodide or methyl bromide or other alkylating agents (especially ethyl iodide or ethyl bromide) in a known manner.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1)=O.Cl>COCCOC.O>[O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:3]=[CH:20]/[CH:22]1[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:25](=[O:36])[CH2:24][S:23]1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: O=CC1SCC(=O)N1CCCCCCC(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Temperature: 25 °C

Procedure:
Dimethyl 2-oxo-4-phenylbutylphosphonate (1 molar equivalent) is added dropwise over a 1/2 hour period to a stirred suspension of sodium hydride (2equivalents) in 1,2-dimethoxyethane maintained at or below 20° C. To the resulting reaction mixture is slowly added 7-(2-formyl-4-oxo-3-thiazolidinyl)heptanoic acid (1 molar equivalent) with good stirring and cooling (sufficient to maintain a reaction temperature at or below 20° C.). Upon completing this addition, the reaction is stirred at ambient temperature for 1 hour, then heated at reflux for 1/2 hour, cooled to room temperature, and diluted with water. The aqueous mixture is acidified with dilute hydrochloric acid and extracted with ether. The organic extract is dried over sodium sulfate, filtered, and evaporated in vacuo at 40° C. leaving the title compound as an oily residue which is purified chromatographically on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:28]4[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Reactant: NCCNCc1ccncc1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCNCc4ccncc4)nc3NC2=O)c1
Yield: 13 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1423 g (0.941 mmol) of N-(4-picoly)ethylenediamine were reacted. The residue was chromatographed eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0162 g (13%) of the title compound: HPLC=92% pure.