Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=2)[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH:39][C:2]3[N:7]=[C:6]4[N:8]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][O:12]5)[N:9]=[CH:10][C:5]4=[C:4]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=4)[N:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3c2cnn3C2CCCCO2)c1
Temperature: 200 °C

Procedure:
N-(3-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (30 mg, 0.078 mmol), 4-(4-methylpiperazin-1-yl)aniline (16 mg, 0.084 mmol)) and potassium carbonate (25 mg, 0.077 mmol) were dissolved in t-butyl alcohol (5 mL) in a sealable microwave compatible reaction tube, then Pd2(dba)3 (1.5 mg, 0.002 mmol) and Xantphos (2 mg, 0.004 mmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (40 min, 200° C., 3 atm). The compound was purified by column chromatography. 1H NMR (400 MHz, CD3OD): δ 8.66 (s, 1H), 8.29 (s, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.72 (m, 3H), 7.51 (t, 1H, J=8.4 Hz), 6.98 (m, 2H), 6.51-6.39 (m, 2H), 5.90 (d, 1H, J=8.8 Hz), 5.80 (dd, 1H, J=2.0 and 9.6 Hz), 4.06 (m, 1H), 3.79 (m, 1H), 3.15 (m, 4H), 3.02 (m, 1H), 2.62 (m, 5H), 2.34 (s, 3H), 2.12 (m, 1H), 1.94 (m, 1H), 1.83-1.70 (m, 2H); ESI-MS: 539.30 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH2:17]=[O:18].[OH-].[K+]>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:17][OH:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(SCO)cc(C(C)(C)C)c1O
Reaction time: 13 h

Procedure:
To a stirred solution of 28.6 g of 2,6-di-tert-butyl-4-mercaptophenol and 9.74 g of 37% aqueous formaldehyde in 100 ml of methyl alcohol was added several drops of a 10 M potassium hydroxide solution. The reaction mixture was stirred for 13 hours and the volatiles were removed in vacuo. The residue was recrystallized from petroleum ether to give a white solid, m.p. 79°-82° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=O)[N:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:14]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>C1COCC1.O>[CH3:1][CH:2]1[CH2:11][N:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH:14]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)C(C)N3C(=O)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of diethyl 2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (300 mg, 0.77 mmol) in THF (10 mL) at rt was added BH3THF complex (3.8 mL, 3.8 mmol) and refluxed for 5 hours. At rt 6N HCl (10 mL) was added and stirred for 0.5 hour before the solution was diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (200 mg, 69%) as a clear oil. MS [M+H]+374.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([CH3:39])[CH:16]([N:21]([CH3:38])[C:22]([C:24]1[S:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)=[O:23])[C:17]([O:19][CH3:20])=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([C:26]3[S:25][C:24]([C:22]([N:21]([CH:16]([CH:15]([CH3:39])[CH3:14])[C:17]([O:19][CH3:20])=[O:18])[CH3:38])=[O:23])=[N:28][CH:27]=3)=[CH:30][CH:31]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Product: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1
Yield: 56 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-tert-butylbenzoyl chloride and intermediate 4. Yield: 56%; 1H NMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.37 (s, 1H), 8.04 (m, 4H), 7.78 (d, 2H), 7.57 (d, 2H), 6.27-4.76 (d, 1H), 3.69 (s, 3H), 3.47-2.95 (s, 3H), 2.35 (m, 1H), 1.33 (s, 9H), 1.11 (bs, 3H), 0.90 (bs, 3H); MS (ESI): m/z 508.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:30])[CH2:28][CH3:29])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and propanoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.[BH4-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][OH:16])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Then, trans-4-(3,5-difluorophenyl)cyclohexane carbaldehyde (112 g) was dissolved in ethanol (224 mL), THF (30 mL), and water (30 mL), and sodium tetrahydroborate (9.4 g) was slowly added to the resultant solution at an outside temperature or 5° C., followed by stirring at an outside temperature of 5° C. for 10 minutes. The reaction solution was slowly poured into 10% hydrochloric acid (450 mL) and stirred for a white, and then an organic layer was separated. An aqueous layer was subjected to extraction with ethyl acetate, and the ethyl acetate extract was combined with the organic layer and washed with saturated brine two times. The mixture was dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 110 g of trans-4-(3,5-difluorophenyl)cyclohexylmethanol as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 3-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:8])[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)OC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
11.7 cm3 of a 1.6M solution of n-butyllithium in hexane is added at -70° C. to a solution of 2.5 g of 5-isopropyloxy pyrrolidin-2-one in 60 cm3 of tetrahydrofuran, while maintaining the temperature between -70° C. and -65° C. Agitation is carried out for 30 minutes under these conditions then a solution of 2.46 g of benzoyl chloride in 8 cm3 of tetrahydrofuran is added, maintaining the temperature between -65° C. and -70° C. The temperature is allowed to return to the ambient over 2 hours. After evaporation to dryness and then chromatography on silica (eluent: ethyl acetate-n-hexane 1-3), 2.78 g of the product sought is obtained.
Reaction SMILES: ClCCl.[CH3:4][C:5]1[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:38][N:39]=[C:40]=[O:41]>C(OCC)(=O)C>[CH3:38][NH:39][C:40]([N:21]1[CH2:22][CH2:23][N:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=3[CH3:4])=[CH:14][CH:13]=2)(=[O:16])=[O:17])[CH:19]([C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)[CH:20]1[CH3:24])=[O:41]
Reactant: CN=C=O
Reactant: Cc1ccccc1COc1ccc(S(=O)(=O)N2CCNC(C)C2C23OCC(C)(CO2)CO3)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a dichloromethane (5 ml) solution of 1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-3-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine (compound of formula XLV, 1.78 g, 3.64 mmol) at about 0° C. was added methyl isocyanate (0.24 ml, 4.0 mmol). The reaction was allowed to stir for about 0.5 hour at about 23° C., was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate and then was concentrated to give 1.927 g of a compound of formula XLIV.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:54]1C=CC=CC=1.[ClH:60]>CN(C=O)C>[ClH:60].[NH2:54][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[O:40])=[CH:34][C:33]=2[F:52])[CH:28]=[CH:27][N:26]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reactant: c1ccncc1
Agent: Cl
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
Bis-(trifluoroacetoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq) was added to a solution of 1-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) and pyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with 1 N HCl and the aqueous solution extracted with Et2O, discarding the organic layer. The aqueous layer was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with 10% aq LiCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (50 mL) cooled to 0° C. and treated with anhydrous HCl (4N, 10 mL, 40 mmol, 7.8 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 h resulting in a heterogeneous solution. The solution was filtered and the solid washed with Et2O and dried in vacuo to afford the title compound (1.38 g, 63%) as a solid. 1H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.65 (s, 1H), 7.97-8.00 (m, 1H), 7.83-7.90 (m, 3H), 7.35-7.48 (m, 4H), 7.15-7.21 (m, 2H), 6.70-6.72 (m, 1H), 6.16-6.17 (m, 1H), 3.77 (s, 2H); MS (ESI+) m/z 399 (M+H)+. HRMS (ESI+) calcd.: 399.1269. found: 399.1258. Elem analysis for C20H16N4O3F2 1.0 HCl . . . 0.22H2O
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16].[OH-].[K+].O1CCOCC1>CCOCC>[CH2:5]([O:4][C:2]([O:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(=NO)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#CC(=NOC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A solution of benzyl chloroformate (5.1 g.) in ether (40 ml.) was added to a solution of 2-hydroxyimino-2-phenylacetonitrile (4.4 g.) in a mixture of a 1N potassium hydroxide aqueous solution (30 ml.) and dioxane (10 ml.) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and for 4 hours at room temperature. The ether layer was separated from the reaction mixture and the aqueous layer was further extracted with ether. Both ether layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off and n-hexane was added to the residue. The precipitated crystals were collected by filtration to give 2-benzyloxycarbonyloxyimino-2-phenylacetonitrile (5.2 g.), mp 73° to 75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=[C:5](SC)[N:4]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(SC)nc1OC
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cncnc1OC

Procedure:
A mixture of 2.2 g of methyl 4-methoxy-2-(methylthio)pyrimidine-5-carboxylate, 15 g of Raney nickel (washed with methanol to remove water) and 200 mL of methanol was stirred under 1 atm hydrogen overnight. Conversion was incomplete by LCMS so the mixture was filtered and treated with 15 g of fresh Raney nickel under hydrogen overnight. After filtration and concentration under reduced pressure, purification by flash chromatography (0%-10% ethyl acetate in hexanes) gave the product as white crystalline solid: MS (m+1)=169.1; 1H NMR (400 MHz, CDCl3) 9.0 (s, 1H), 8.82 (s, 1H), 4.1 (s, 3H), 3.9 (s, 3H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[NH:10][C:9](=[O:11])[NH:8][C:7](=[O:12])[C:6]=1[N+:13]([O-])=O>C(O)(=O)C.[Zn]>[NH:10]1[C:5]2[CH:4]=[CH:3][NH:13][C:6]=2[C:7](=[O:12])[NH:8][C:9]1=[O:11]
Reactant: CN(C)/C=C/c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2[nH]ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A suspension of 6-[(e)-2-(dimethylamino)vinyl]-5-nitropyrimidine-2,4(1H,3H)-dione (1.43 g, 6.36 mmol) in acetic acid (23 mL) was heated to 80° then zinc dust (2 g, 30.77 mmol) was added slowly over 1 h. The resulting suspension was heated for a further 1 h then allowed to cool to room temperature. The solid was collected by filtration then washed with acetic acid. The solid was transferred to a beaker and washed with water (25 mL), collected then dissolved in sodium hydroxide (5%, 10 mL). This solution was warmed to 70° and stirred for 30 min Acetic acid was added until pH 5-6 then the precipitate collected and washed with cold water then ethanol. The resultant solid was dried in vacuo to furnish 1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (0.62 g, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C:17](=[CH:28][O:29][CH2:30][CH3:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:32]([O:27][C@H:18]1[C:17](=[CH:28][O:29][CH2:30][CH3:31])[CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]12[CH3:20])[C:24]1[CH:25]=[CH:26][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:12][CH2:13]3)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Yield: 86 %

Procedure:
A solution of 3 (194 mg), acetic anhydride (1 mL) in pyridine (3ml) was stirred at rt overnight under N2. Reaction was poured into saturated aqueous NaHCO3 (150 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×20 cm column of silica gel using hexanes/EtOAc (4:1) as eluent gave 183 mg (86%) of 4 as a white solid: TLC, T-2, Rf0.67.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:31]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][CH2:29][OH:31])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane (Prepn. 11) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane (Prepn. 9). The crude was purified by flash chromatography (SiO2, n-hexane/acetone 80/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.25 (t, 1H), 3.86-3.70 (m, 8H), 3.35 (m, 2H), 1.91-0.42 (m, 23H), 0.75 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:16]1N=NC(N)=[C:18](C2C=CC=CC=2)[CH:17]=1.ClCC(=O)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:5]2[N:6]([CH:16]=[C:17]([CH3:18])[N:8]=2)[N:7]=1
Reactant: Nc1cc(-c2ccccc2)c(Cl)nn1
Reactant: Nc1nnc(Cl)cc1-c1ccccc1
Agent: CC(=O)CCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn2nc(Cl)c(-c3ccccc3)cc2n1

Procedure:
The mixture of 6-chloro-5-phenyl-pyridazin-3-yl-amine and 6-Chloro-4-phenyl-pyridazin-3-yl-amine (intermediate example Int-1-0, step 3, 65 g=316 mmol) in 65 mL tetrahydrofurane and 650 mL water was heated with 74.5 g (800 mmol) chloroacetone in analogy to the synthesis of the intermediate example Int-1-0, step 4, for 18 hours at reflux. After the usual work up and purification of the residue by chromatography (Biotage Isolera, Kronlab 8 cm, eluents: dichloromethane/methanol) and subsequent crystallization (methyl-tert.butylether/hexane) 11.69 g (30.4%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[N:10]=[N:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=12.CCN=C=NCCCN(C)C.[F:36][C:37]1([F:46])[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]1.N1C2C(=NC=CC=2)N(O)N=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:36][C:37]1([F:46])[CH2:42][CH2:41][CH:40]([C:43]([N:6]2[CH2:7][C@@H:2]([CH3:1])[N:3]([C:9]3[N:10]=[N:11][C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:13]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=34)[CH2:4][C@@H:5]2[CH3:8])=[O:44])[CH2:39][CH2:38]1
Reactant: C[C@@H]1CN(c2nnc(-c3ccccc3)c3ccncc23)[C@@H](C)CN1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)[C@@H](C)CN1c1nnc(-c2ccccc2)c2ccncc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To racemic trans 4-(2,5-dimethylpiperazine-1-yl)-1-phenylpyrido[3,4-d]pyridazine 44 (360 mg, 1127 μmol) dissolved in 4 mL of DMF was added EDCI (259 mg, 1.35 mmol), 4,4-difluorocyclohexanecarboxylic acid (204 mg, 1.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (184 mg, 1.35 mmol) (HOAT), and sodium carbonate (239 mg, 2.25 mmol). The reaction was stirred at RT for 4 h, and the solvent was removed in vacuo. The crude reaction mixture was dissolved in 100 mL of ethyl acetate and washed with 1×25 mL of water, 1×25 mL of sat. NaHCO3, and 1×25 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purified by column chromatography to isolate racemic (4,4-difluorocyclohexyl)(trans-2,5-dimethyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 45. MS 465.2 (calc'd) 466.1 (M+H, found).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:21]([F:24])([F:23])[F:22])([OH:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[C:11]=1[O:18][CH3:19])([CH3:9])[CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:20])([C:21]([F:24])([F:23])[F:22])[CH:4]=[O:3])=[C:11]([O:18][CH3:19])[C:12]=1[F:17]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c(C(C)(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F

Procedure:
1.00 g (2.59 mmol) of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester is dissolved in 9.5 ml of diethyl ether and mixed in portions at 0° C. with 73.7 mg (1.94 mmol) of LiAlH4. Stirring is continued at 0° C., and a TLC is taken every quarter hour. After 40 minutes of stirring at 0° C., the reaction mixture is mixed drop by drop with 2.4 ml of saturated NaHCO3 solution while being cooled in an ice bath. It is stirred for 30 minutes while being cooled in an ice bath, and it is stirred vigorously overnight at room temperature. The precipitate is suctioned off, washed with ethyl acetate, and the filtrate is concentrated by evaporation in a rotary evaporator. After the residue is chromatographed on a Flashmaster, 560.2 mg is obtained. In this case, this is a 3:2 mixture of the aldehyde with the starting ester.