Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:11][C:12](=O)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[C:20]([C:31]([F:34])([F:33])[F:32])=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]=2[C:15]1=[O:35]>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:16]3[C:15](=[O:35])[N:14]([CH2:13][C:12](=[O:11])[N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:19][CH2:18][C:17]=3[C:20]([C:31]([F:34])([F:32])[F:33])=[N:21]2)=[CH:24][CH:25]=1
Reactant: COC(=O)CN1CCc2c(C(F)(F)F)nn(-c3ccc(OC)cc3)c2C1=O
Reactant: C1CCNC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CC(=O)N2CCCC2)CC3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Part A: Pyrrolidine (0.152 mL, 1.826 mmol) was dissolved in methylene chloride (6 mL) and cooled to 0° C. 2M Trimethylaluminum (0.652 mL, 1.304 mmol) was added to the reaction and stirred for 30 min at 0° C. [1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-acetic acid methyl ester (0.100 g, 0.261 mmol) was added and the reaction was stirred overnight at rt. The reaction was quenched with water (100 mL), extracted into methylene chloride (3×50 mL), washed with brine (1×50 mL), dried over MgSO4, concentrated, and purified, by flash chromatography using 0–100% ethyl acetate/hexanes gradient and methanol flush as eluents, followed by further purification by reverse phase HPLC. Freeze-drying afforded 0.052 g (47%): 1H NMR (CDCl3) δ 7.38 (d, j=8.8 Hz, 2H), 6.87 (d, j=9.1 Hz, 2H), 4.15 (s, 2H), 3.77 (t, j=6.8 Hz, 2H), 3.76 (s, 3H), 3.40(t, j=6.8 Hz, 2H), 3.33 (t, j=6.8 Hz, 2H), 3.00(t, j=6.8 Hz, 2H), 1.92–1.85 (m, 2H), 1.82–1.73 (m, 2H) ppm; Mass Spec 423.3(M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl>O.CO>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc1Cc1cccc(NC(N)=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCN1CCCC1Cc1cccc(NC(N)=O)c1
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A suspension of 1.25 g (4.6 mmol) of 1-butyl-2-(3'-ureidobenzyl)pyrrole, prepared, for example, as described in Preparation 6D, in a mixture of 75 ml of water, 75 ml of methanol and 10 ml of a 1N solution of hydrochloric acid in methanol, was hydrogenated at 45 p.s.i. in the presence of 1 g of 5% rodium on activated alumina as catalyst, for 1 hour. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The aqueous residue was treated with concentrated ammonium hydroxide until an alkaline pH was obtained, and the product extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (2×50 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 100 g of silica gel, using an (80:20) mixture of methylene chloride-[chloroform-methanol-ammonium hydroxide (60:10:1)] as the eluting system, thus obtaining 550 mg (44%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)pyrrolidine, which was recrystallized from acetone-hexane. M.P. 80°-83° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30](=O)[CH3:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:30]([CH3:31])[CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:14])[CH3:2]
Reactant: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Yield: 124.4 %

Procedure:
To a 25 ml volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (500 mg), toluene (1.75 ml), and 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4) (470 mg) were added. Water was removed by azeotropic distillation at 45-50° C. under 100 mmHg for 1.5 hours. To the mixture, toluene (1.75 ml) was added, and water was removed by azeotropic distillation at 60° C. under 120 mmHg for 6 hours. The reaction mixture was concentrated under reduced pressure to give 1.109 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC.O>C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc(F)cc2)c1
Yield: 88.8 %

Procedure:
A mixture of 5-bromo-thiophene-3-carboxylic acid ethyl ester (1.0 g, 4.5 mmol), 4-fluorophenylboronic acid (0.88 g. 6.4 mmol), potassium carbonate (1.75 g, 12 mmol) and tetrakistriphenylphosphinepalladium(0) (0.2 g, 4 mole %) in a 50:50 mixture of DME/H2O (10 mL) was heated at reflux temperature overnight under a nitrogen atmosphere. The resulting reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over sodium sulfate and rotary evaporated. The residue was purified by flash chromatography (silica gel; 2% acetone/hexane) to obtain 5-(4-fluorophenyl)-3-thiophenecarboxylic acid ethyl ester as an oil (1.0 g, 88%). MS: m/z=251 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(Cl)cc2)cc1
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
(a) 0.312 g of 50% sodium hydride is suspended in 10 ml of anhydrous dimethylformamide, and 1.16 g of 4-[N-(4-chlorophenyl)formimidoyl]phenol is added to the suspension at 20° to 25° C. with stirring. Subsequently over a period of 15 minutes, 1.27 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at the same temperature with stirring. The mixture is stirred at the same temperature for 30 minutes, then at 50° to 55° C. for 2 hours and thereafter at 80° C. for 3 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5% aqueous solution of sodium hydroxide and then with water. After drying, the solvent is distilled off to give 1.5 g of ethyl 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.ClC1C(C2C=CC(Cl)=CC=2)=CC2N(C(=O)N(CC3C=NC(C(F)(F)F)=CC=3)N=2)N=1>>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:9]2[C:8](=[O:11])[N:6]3[N:7]=[C:2]([Cl:1])[C:3]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[CH:4][C:5]3=[N:10]2)=[CH:22][CH:23]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Yield: 60 %

Procedure:
The title compound (469 mg, 60%) was prepared from 6-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (500 mg, 1.78 mmol) and 1-chloromethyl-4-trifluoromethyl benzene (425 mg, 1.78 mmol) according to the procedures described for 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 8E). LC/MS (Method C): retention time=3.91 min, (M+H)+=439.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:6]=1)[OH:4].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:38]=[CH:37][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[Cl:17][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:38]=[CH:37][C:28]([CH2:29][CH:30]5[S:34][C:33](=[O:35])[NH:32][C:31]5=[O:36])=[CH:27][CH:26]=4)[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1cc(-c2ccc(Cl)c(Cl)c2)no1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cc(-c5ccc(Cl)c(Cl)c5)no4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1S)-2-amino-1-[3-(3,4-dichloro-phenyl)isoxazol-5-yl]ethanol (which was obtained in Example 109) and 5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 106 and was obtained as a white solid (0.22 g, 48% yield), mp 110° C.; MS (ES) m/z: 561 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.38 (m, 2H), 1.89 (m, 2H), 3.32–2.67 (m, 7H), 3.60 (m, 2H), 4.74 (m, 1H), 4.85 (m, 1H), 6.85 (d, 1H), 7.02 (d, 1H), 7.11 (s, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 8.13 (s, 1H).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[N:27]([CH3:28])[CH:26]=[CH:25][C:19]3=[N:20][C:21]=2[C@@H:22]([NH2:24])[CH3:23])[CH:13]=[CH:12][N:11]=1)C1C=CC=CC=1.Cl.N[C@H](C1N=C2C=CN(C)C2=CC=1C1C=CN=C(O)C=1)C.[NH2:50][C:51]1[N:56]=[C:55]([NH2:57])[C:54]([C:58]#[N:59])=[C:53](Cl)[N:52]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:50][C:51]1[N:56]=[C:55]([NH2:57])[C:54]([C:58]#[N:59])=[C:53]([NH:24][C@H:22]([C:21]2[N:20]=[C:19]3[CH:25]=[CH:26][N:27]([CH3:28])[C:18]3=[CH:17][C:16]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([OH:9])[CH:15]=2)[CH3:23])[N:52]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnc(OCc2ccccc2)c1
Agent: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnc(O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccnc(O)c1
Temperature: 120 °C
Yield: 46.3 %

Procedure:
A mixture of (S)-1-(6-(2-(benzyloxy)pyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (155 mg, 0.393 mmol) and (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyridin-2-ol hydrochloride (120 mg, 0.393 mmol) along with 2,4-diamino-6-chloropyrimidine-5-carbonitrile (100 mg, 0.590 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.18 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was dissolved in MeOH (10 mL). Pd/C (10%, 700 mg) was added and the reaction mixture was maintained under an atmosphere of hydrogen for 30 minutes. The mixture was filtered through Celite and concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 20-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (73 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.32 (m, 3 H), 3.80 (br s, 3 H), 5.58 (quin, J=6.71 Hz, 1 H), 6.31 (d, J=6.83 Hz, 1 H), 6.48 (br s, 2 H), 6.52-6.63 (m, 5 H), 6.66 (d, J=7.81 Hz, 1 H), 7.52 (d, J=6.35 Hz, 1 H), 7.72 (d, J=2.93 Hz, 1 H), 7.80 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H19N9O, 402; found 402.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Br-:31].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 44.6 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0808 g, 0.264 mmol) and 3-bromopropyl phenyl ether (0.070 mL, 0.444 mmol) in 2MeOH/3 CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0613 g, 44.7%). EI-MS m/z 440(M+) Rt (2.05 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([O:7][C:8]([C:10]2([OH:23])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH2:3]1.ClC[CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].[CH2:36]1COCC1>>[CH:8]([O-:9])=[O:7].[OH:23][C:10]1([C:8]([O:7][C@@H:4]2[CH2:5][CH2:6][N+:2]([CH3:36])([CH2:1][CH2:26][CH2:27][C:28](=[O:29])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:3]2)=[O:9])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: C1CCOC1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CN1CC[C@@H](OC(=O)C2(O)c3ccccc3-c3ccccc32)C1
Product: C[N+]1(CCCC(=O)c2ccccc2)CC[C@@H](OC(=O)C2(O)c3ccccc3-c3ccccc32)C1
Product: O=C[O-]
Yield: 7 %

Procedure:
0.575 g (1.858 mmol) of 9-Hydroxy-9H-fluorene-9-carboxylic acid (3R)-1-methylpyrrolidin-3-yl ester (Intermediate I-10) and 1.018 g (5.576 mmol) of 4-chloro-1-phenylbutan-1-one in 6 ml of THF were refluxed for 20 days. After this time THF was poured off, and the residue was washed with THF in order to eliminate the alkylating agent. The product obtained (234 mg) was purified by preparative HPLC-MS to give 65 mg (7%) of the title compound (mixture of two stereoisomers) as a formate.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].CS(C)=O.[OH-].[K+].[CH2:37](Br)[CH:38]=[CH2:39]>O>[C:6]([S:3]([N:2]([CH2:39][CH:38]=[CH2:37])[CH3:1])(=[O:5])=[O:4])([C:7]([C:8]([C:9]([C:10]([C:11]([C:12]([C:13]([F:16])([F:15])[F:14])([F:18])[F:17])([F:19])[F:20])([F:21])[F:22])([F:23])[F:24])([F:25])[F:26])([F:27])[F:28])([F:30])[F:29]
Reactant: C=CCBr
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 85.3 %

Procedure:
A one-liter three-neck flask equipped with magnetic stirring and an addition funnel was charged with 150 g of N-methylperfluorooctanesulfonamide and 570 g of dimethyl sulfoxide, and the mixture was stirred for a few minutes until the solid dissolved. To this stirred solution was added a solution of 25 g of potassium hydroxide in 25 g of water. This mixture was allowed to stir for 30 min, then 46 g of allyl bromide was added dropwise via the addition funnel. An exotherm was noted after a few minutes. The reaction mixture was allowed to stir for 5.5 hr, during which time a white solid precipitated from solution. This solid was isolated by filtration, washed with 350 mL dimethyl sulfoxide, and dissolved in 450 g of 1,1,2-trichlorotrifluoroethane. This solution was transferred to a separatory funnel, washed with four 200 mL portions of water, and dried over anhydrous sodium sulfate. After removal of solvent by distillation at atmospheric pressure, the product was vacuum distilled to yield 138 g of C8F17SO2N(CH3)CH2CH═CH2, b.p. 98° C. at 0.4 torr (50 Pa) to 105° C. at 0.7 torr (90 Pa). The product was a clear, almost colorless liquid which solidified to a white, waxy solid upon standing at room temperature.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH3:16][C:6]1[CH:7]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:17]=[C:18]([NH2:20])[S:19][CH:2]=1
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(S(C)(=O)=O)cc(C)c1-c1csc(N)n1
Yield: 46.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylsulfonyl)phenyl)ethanone (7.60 g, 24.9 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.6 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (20 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(methylsulfonyl)phenyl)thiazol-2-amine (3.28 g) as yellow solids in 47% yield: 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 2 H), 6.34 (s, 1 H), 5.19 (m, 1 H), 3.04 (s, 3 H), 2.26 (s, 6 H).
Reaction SMILES: Cl[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:11][C:10]3[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=3[N:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
8-Chlorotheophylline (3.5 g) and piperazine-1-carboxylic acid tert-butyl ester (11.69 g) were mixed, and stirred at 110° C. overnight. Then, the reaction mixture was diluted with ethyl acetate and water, insoluble white solid was collected by filtration, and washed with ethyl acetate to give 3.65 g of the title compound.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:13]=[C:12]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:11]=1>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([NH:25][C:12]2[N:11]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Product: CN(C)C=Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile (0.0008 mol). The mixture was stirred at room temperature for 2 days and then concentrated. The crude product was purified by flash chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The desired fraction was collected and the solvent was evaporated. The resulting residue was triturated with hexane, yielding 0.15 g (42%) of N′-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethyl-methanimidamide (comp. 26; mp. 175-180° C.).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:19]([CH2:21][CH2:22][NH:23][CH2:24][CH2:25][OH:26])[NH2:20].[C:27](=[O:30])(O)[O-].[K+].[F-].[K+]>CS(C)=O>[OH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:19]1[C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:7](=[O:18])[C:8]4[C:13]([C:14]([C:15]=23)=[N:20]1)=[CH:12][CH:11]=[CH:10][C:9]=4[NH:19][CH2:21][CH2:22][NH:23][CH2:24][CH2:27][OH:30]
Reactant: NNCCNCCO
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: O=C([O-])O
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2c(NCCNCCO)cccc2-c2nn(CCNCCO)c3cccc1c23
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A mixture of 11.1 g (40 mmol) of 1,5-dichloro-9,10-anthracenedione, 13.1 g (110 mmol) of 2-[(hydrazinoethyl)amino]ethanol, 4 g of anhydrous potassium bicarbonate, 1 g of anhydrous potassium fluoride, and 110 ml of dimethyl sulfoxide is stirred at 70° C. overnight. The mixture is chilled and the solids are collected by filtration, washed with water, then thoroughly with acetonitrile to give a residue that is crystallized from 2-propanol to leave 2.6 g of product. The hydrochloride salt is prepared as described in Example 3; mp 272°-273° C. (decomposition).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[C:19]1[C:26]([F:27])=[CH:25][C:22](C#N)=[C:21]([O:28][CH3:29])[CH:20]=1.CCOC(C)=O.[CH3:36][N:37](C=O)C>>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:22]1[CH:25]=[C:26]([F:27])[C:19]([C:36]#[N:37])=[CH:20][C:21]=1[O:28][CH3:29])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(F)c(F)cc1C#N
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c(F)cc1C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A suspension of NaH (60% in mineral oil, 0.33 g, 8.3 mmol) in dry DMF (20 mL) was stirred and cooled to 0° C., and di-tert-butyl malonate (1.5 g, 7.1 mmol) was added. The mixture was allowed to warm to room temperature before addition of 4,5-difluoro-2-methoxybenzonitrile (1.0 g, 5.9 mmol). The mixture was heated at 80° C. for 4 h with stirring, then the reaction mixture was cooled to room temperature and poured into a mixture of ice-water (100 mL) and AcOEt (100 mL). The layers were separated, and the organic layer was washed successively with water, and brine, then dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 0→10%) to give the di-tert-butyl(4-cyano-5-fluoro-2-methoxyphenyl)propanedioate. LCMS: [(M+1)-t-Bu,CO2-t-Bu]+=210.1; tR=2.2 min.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:22])[C:4]([CH:11]([OH:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].C([O-])(=O)C.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)C>CC(C)=O.S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:3](=[O:22])[C:4]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC(=O)OCCCCCC(O)C1=C(C)C(=O)C(C)=C(C)C1=O
Agent: O=[Cr](=O)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCCCCCC(=O)C1=C(C)C(=O)C(C)=C(C)C1=O

Procedure:
A solution of 2,3,5-trimethyl-6-(6'-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone formula IV-3 wherein R=H3C, n=4, in the form of acetate at --CH2OH) (0.74 part) in acetone (20 volume parts) was oxidized at 5° C. for 5 minutes with Jones reagent (0.6 volume part) prepared by dissolving chromic trioxide (26.72 parts) in concentrated sulfuric acid (23 volume parts) diluted with water to a volume of 100 volume parts. The resulting precipitate wad decomposed with water, and the product was taken up with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to column chromatography on silica gel and eluted with methylene chloride and the resulting product was crystallized from petroleum ether to give 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (formula IV-1 wherein R=H3C, n=4, in the form of acetate) (0.638 part) as yellow crystals melting at 57° C.