Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][Cl:12])=[CH:9][CH:8]=1>O1CCCC1.CCOCC>[ClH:12].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:3][C:2](=[NH:4])[NH2:1])=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC(=N)N)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A suspension of thiourea (38 g, 50.0 mmole) in dry tetrahydrofuran (40 ml) was cooled to 0° C. under argon and was treated dropwise with 4-methoxybenzylchloride (8.0 g, 50.0 mmole). After the addition was completed, the cooling bath was removed and the reaction was allowed to stir at room temperature for 2 hours. It was then heated at 60-65° C. for 4 hours whereupon a colorless voluminous precipitate was formed. The reaction was allowed to cool down to room temperature and was, diluted with anhydrous ether. The solid was filtered off and washed with anhydrous ether to give 10.92 g of 2-(4-methoxybenzyl)-2-thiopseudourea, hydrochloride, melting point 161-163.5° C. Analysis Calc'd. for C9H12N2OS.HCl: C, 46.45; H, 5.63; N, 12.04; S, 13.78; Cl, 15.23. Found: C, 46.48; H, 5.64; N, 12.25; S, 13.74; Cl, 15.31.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:11]2[CH2:13][CH2:12]2)=[N:8][O:9][CH:10]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O.O>[CH:11]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1conc1C1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1conc1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.6 g (31 mmol) of 3-Cyclopropyl-isoxazole-4-carboxylic acid ethyl ester were slowly added to a solution of 6.1 g (93 mmol, 85% purity) of potassium hydroxide in ethanol/water (1:3, 100 ml) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with water, acidified (pH=2) with 20% aqueous HCl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed to yield 4.7 g (94%, 95% purity) of the title compound which did not need further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.S(Cl)([Cl:19])(=O)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[C:9]=2[Cl:19])[N:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2nc(OC)cc(C)c2c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c2c(Cl)c(OC)ccc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 500 ml, four-necked round bottom flask equipped with a mechanical stirrer, condenser, thermowatch and addition funnel was charged with 2,6-dimethoxy-4-methylquinoline (9) (17.9 g, 0.09 moles) and glacial acetic acid (120 ml). The resulting solution was heated to 60° C., then a solution containing sulfuryl chloride (13.4 g, 0.01 moles) and glacial acetic acid (40 ml) was added over 20 minutes. Reaction temperature was held between 60-65° C. during this addition. The resulting solution was stirred for 1 hour at 60-65° C., then additional sulfuryl chloride (3.8 g, o,028 moles) in glacial acetic acid (10 ml) was added. The mixture was stirred an additional 30 minutes, then it was poured into 300 ml of water. The slurry was cooled to 5° C., the product removed by suction filtration, washed with water and air dried. Yield was 18.4 g (86%); mp=97-100° C.; purity by HPLC=89.7 area %.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=3)[CH2:37][CH2:36]2)[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50].C(N(CC)CC)C.CN(C)C=O>O>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([N:38]2[CH2:39][CH2:40][N:35]([C:28]3[C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[CH:22]=[N:21][N:20]([C:1]([C:14]6[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=6)([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:8]6[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=6)[CH:24]=5)[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH2:36][CH2:37]2)[CH:42]=1)=[O:53]
Reactant: Nc1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of 100 mg 3-{4-[6-(1-trityl-1H-pyrazol-4-yl)quinazolin-4-yl]piperazin-1-yl} phenylamine obtained in Example 825, 30 mg pivaloyl chloride, 50 μl triethylamine and 10 mL N,N-dimethyl formamide was stirred at room temperature for 15 minutes. Water was added to the mixture which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 91 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][C:4]([CH3:12])([CH3:11])[O:3]1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:14]1([C:8]([CH:6]2[CH2:5][C:4]([CH3:12])([CH3:11])[O:3][C:2]([CH3:1])([CH3:13])[CH2:7]2)=[O:10])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)O1
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,6,6-tetramethyl-tetrahydro-pyran-4-carboxylic acid (1.4 g, 6.8 mmol) and benzotriazole (2.4 g, 20.3 mmol) in 34 mL of DCM was added thionyl chloride (0.55 mL, 7.4 mmol) dropwise and the mixture was allowed to stir for 8 hrs at RT. The mixture was filtered to remove the ppt and the filtrate washed with saturated NaHCO3 (2×40 mL) and then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated to give 1.9 g (97%) of a white ppt.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([N:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:25][CH3:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:27]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[N:25]([CH3:26])[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 198 mg, 1.087 mmol), (1S,2S)-1-N,1-N-dibenzyl-2-N-methylcyclopentane-1,2-diamine (291 mg, 0.988 mmol) and DIPEA (518 μl, 2.97 mmol) in DMSO (3.3 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was diluted with ethyl acetate (20 ml), washed with a saturated solution of sodium bicarbonate (3×20 ml), brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-15% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][S:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:18][CH3:19])[C:10]=1[CH:20]=[CH2:21])(=[O:8])=[O:7].[CH:22]([N:25]1[CH:29]=[CH:28][C:27](=O)[NH:26]1)([CH3:24])[CH3:23].[C:31]([O-])([O-])=[O:32].[K+].[K+]>C1(C)C=CC=CC=1.COCCOC>[CH3:31][O:32][C:29]1[N:25]([CH:22]2[CH2:24][CH2:23]2)[N:26]=[CH:27][C:28]=1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([S:6]([CH3:5])(=[O:7])=[O:8])=[C:10]([CH:20]=[CH2:21])[C:11]=1[O:18][CH3:19])=[O:15]
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1OC
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1ccc(=O)[nH]1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: C=Cc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C3CC3)c2OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
SOCl2 (1.2 g, 10 mmol) was added to a solution of 4-methylsulfonyl-2-methoxy-3-vinylbenzoic acid (1.6 g, 6 mmol) in toluene (60 ml) and the mixture was heated at reflux for 2 h. The mixture was then concentrated and the product was added to a solution of N-isopropylpyrazolone (6 mmol), K2CO3 (1.6 g, 11.6 mmol) in DME (30 ml) and the mixture was stirred at RT overnight. The mixture was subsequently heated at reflux for 2 h and concentrated and the residue was dissolved in H2O. The H2O phase was extracted 3× with CH2Cl2, and the combined organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:16])[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:19].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]([CH3:16])[C:13]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH3:19])=[O:15])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)O
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C(C)(C)C)cc1)C(=O)NC(C)c1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 12 h
Yield: 93.4 %

Procedure:
3-(4-t-Butyl-phenyl)-2-methylacrylic acid (1.1 eq, 0.14 mmol, 31.00 mg) and (R)-N-[4-(1-Amino-ethyl)-2-fluorophenyl]methanesulfonamide (1 eq, 0.13 mmol, 30 mg) were dissolved in DMF. DEPC (1.2 eq, 0.16 mmol, 23.67 μl) and TEA (2 eq, 0.26 mmol, 36.24 μl) were added into the mixture. The reaction mixture was stirred for 12 hrs. DMF was removed in vacuo. The residue was extracted with ethyl acetate and H2O. A combined organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EtOAc=1:1) to yield the title compound (52.53 mg, 93.5%) as a white solid.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:41](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>>[Si:41]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
This compound was prepared from 5'-O-(4,4'-dimethoxytrityl)-thymidine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)[CH:18]=3)[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH3:29][C:26]1([CH3:30])[O:25][C@H:24]([CH2:23][O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)[CH:21]=[CH:20]3)[CH2:28][O:27]1
Reactant: COC(=O)c1ccc(OCc2ccc3cc(OC[C@@H]4COC(C)(C)O4)ccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](COc2ccc3cc(COc4ccc(C(=O)O)cc4)ccc3c2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid methyl ester (0.46, 1.09 mmol) in THF/water (10 ml of a 1:1 mixture) is added lithium hydroxide (0.15 g, 3.57 mmol). The reaction mixture is stirred at room temperature overnight, then at 70° C. for 24 h. The reaction mixture is cooled to room temperature, neutralized with 1.5 M HCl and the white solid obtained is collected by vacuum filtration, washed with water and dried under vacuum to afford 4-[6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid. [M]− 407.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].Br[CH:22]([CH3:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH:22]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])([CH3:24])[CH3:23]
Reactant: COCc1cc(C(=O)OC)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)OC)ccc1OC(C)C
Temperature: 90 °C
Yield: 98.4 %

Procedure:
Methyl 4-hydroxy-3-(methoxymethyl)benzoate (9.50 g; 48.42 mmol; 1 eq.) was dissolved in DMF (142.50 mL). Then K2CO3 (26.77 g; 193.68 mmol; 4 eq.) and 2-bromopropane (18.18 mL; 193.68 mmol; 4 eq.) were added to the reaction mixture. It was heated to 90° C. for 3 hours. The reaction mixture was cooled to RT and diluted with EtOAc. It was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow oil (11.35 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.95-7.84 (m, 2H), 7.13-7.11 (d, J=8.63 Hz, 1H), 4.81-4.69 (sept, J=6.07 Hz, 1H), 4.39 (s, 2H), 3.81 (s, 3H), 3.36 (s, 3H), 1.31-1.29 (d, J=6.01 Hz, 6H). LC/MS (Method B): 239.2 (M+H)+. HPLC (Method A) Rt 4.25 min (Purity: 95.8%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].[O:22]1[CH2:27][C:26](=O)[CH2:25][C:24](=[O:29])[CH2:23]1>C(O)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:25]3[C:24](=[O:29])[CH2:23][O:22][CH2:27][C:26]=3[NH:1][C:2]3[N:3]([CH3:8])[O:4][C:5](=[O:7])[C:6]2=3)=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C1COCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(C(F)(F)F)c1

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 4-fluoro-3-trifluromethylbenzaldehyde and 2H-pyran-3,5(4H,6H)-dione (0.11 g, 1 mmol) were heated in 2 mL of ethanol for 2 days. The reaction mixture was evaporated under reduced pressure and the remaining residue was triturated with methylene chloride. The resulting precipitate was filtered to provide the title compound as the filter cake. 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 4.07 (s, 2H), 4.58 (q, 2H), 4.87 (s, 1H), 7.42 (t, 1H), 7.59 (m, 2H), 10.8 (s, 1H); MS (ESI) m/z 383 (M−H)−; Anal. Calcd for C16H12N2F4O4: C, 51.61; H, 3.22; N, 7.52. Found: C, 51.09; H, 3.11; N, 6.98.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]>CN(C=O)C.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][N:18]([C:2]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: CC1COC2(CCNCC2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC3(CC2)OCC(C)O3)c(C#N)c1

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (2.76 g, 20.4 mmol) and 4-piperidone propylene ketal (3.39 g, 21.5 mmol) in DMF (50 mL) was heated in an oil bath (90° C., 20 h). The mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 50-0% hexane/CHCl3) afforded the title compound (29).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)#[CH:23]>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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH2:23][CH2:22][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(CCc3ccc(F)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.350 g (0.809 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 47 mg (0.040 mmole) tetrakis(triphenylphosphine)palladium(0), 15 mg (0.081 mmole) copper (I) iodide, 5mL degassed toluene, 0.338 mL (2.43 mmole) degassed TEA, and 0.139 mL (1.21 mmole)1-ethynyl-4-fluorobenzene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford a crystalline solid. MS (ES+) 425 (M+1, 100).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1nccs1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nccs4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-thiazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].C[Si]([C:19]#[CH:20])(C)C.C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])#[CH:20]
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(2-trimethylsilyl)ethynyl-3,4-dihydro-4,4-di-methyl-naphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [Br-:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:1].[CH2:2]([P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Decane bromide (7.0 g) and 10 g of triphenylphosphine were stirred at 120° C. under a nitrogen atmosphere for 8 hours. The mixture was recrystallized from acetone-ether to give 14.4 g of colorless, crystalline decyltriphenylphosphonium bromide. IRνmax (CHCl3): 2920, 2850, 1440, 1120, 1000, 680 cm-1
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cu][C:29]#[N:30].C1(C)C=CC=CC=1>ClCCl.C(#N)C>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[O:21])[C:29]#[N:30])=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#C[Cu]
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc2c(C(=O)C#N)cn(CC3CCCCC3)c12
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (5 g, 17.4 mmol) in dichloromethane (100 ml) was added oxalyl chloride (3.04 ml, 34.8 mmol) and the resulting solution stirred overnight. Excess solvent and reagent were then removed by evaporation. To the resulting residue was added copper (I) cyanide (6.2 g, 69.6 mmol), toluene (200 ml) and acetonitrile (10 ml) and the resulting reaction mixture heated at reflux for 7 hours. A further portion of copper (I) cyanide (1.6 g, 17.9 mmol) was then added and the reaction mixture heated at reflux overnight. The reaction mixture was cooled and filtered through a pad of dicalite. The dicalite was washed with acetonitrile and the combined filtrate evaporated to leave a red solid. The solid was purified by flash column chromatography eluting with 50% (v/v) dichloromethane in heptane to afford (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetonitrile (4.7 g, 14.7 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH2:8]([C:5]1[N:4]=[C:3]([CH2:2][N:1]=[CH:12][N:13]([CH3:15])[CH3:14])[O:7][N:6]=1)[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCc1noc(CN)n1
Product: CCc1noc(CN=CN(C)C)n1

Procedure:
A mixture of 26 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 30 ml of dimethylformamide dimethylacetal is heated for 61/2 hours to 80° C. (bath temperature). Then 16 ml of methanol is distilled off and the formed product is purified by bulb tube distillation. 27.9 g (74.8%) of oil with a boiling point of 130°-150° C. (0.05 torr); nD20 : 1.4924.