Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.ClC1[N:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[S:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:6]1[CH:17]=[CH:18][C:19]2[C:24](=[N:23][CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=2[S:34][C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[N:25]=1)[CH3:13])[CH3:12]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a slurry of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 mL anhydrous THF at 0° C. under an atmosphere of N2 was added 2-methyl-malonic acid diethyl ester (0.174 g, 1.0 mmol) dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product from Example 24a (0.047 g, 1.0 mmol), microwave at 120° C. for 1 hour, cooled, partitioned between ethyl acetate and water and neutralized with 1M HCl. The aqueous layer was extracted by ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound. The residue was purified by chromatography on silica eluting with 1% methanol in dichloromethane to give the title compound (0.031 g, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.14 (t, J=7.17 Hz, 3H) 1.52 (d, J=7.35 Hz, 3H) 2.04 (s, 3H) 2.30 (s, 3H) 4.10 (m, 3H) 6.17 (s, br, 1H) 7.04 (m, 3H) 7.26 (d, J=8.82 Hz, 2H) 7.48 (d, J=7.35 Hz, 1H) 7.57 (d, J=8.46 Hz, 2H) 8.45 (d, J=8.46 Hz, 1H) 8.78 (d, J=8.82 Hz, 1H) 9.11 (s, 1H) 10.05 (s, 1H); (ESI+) m/z 501 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([SH:46])=[CH:42][CH:41]=1.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-])([O-])=O.[K+].[K+]>CN(C=O)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]>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([S:46][C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH2:30])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: COc1ccc(S)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: CN(C)C=O
Product: COc1ccc(Sc2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 160 °C
Yield: 19.3 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 4-methoxythiophenol (0.022 mL, 0.18 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), xantphos (10 mg, 0.02 mmol), and K2CO3 (25 mg, 0.18 mmol) in DMF (0.9 mL) was heated at 160° C. for 1 hour. After cooling to room temperature, the mixture was purified by HPLC to give the titled compound as a white solid (9 mg, 15%). 1HNMR (CD3OD) 400 MHz δ: 8.33 (s, 2H), 8.11 (dd, J=4.6, 1.7 Hz, 1H), 7.90 (dd, J=7.7, 1.4 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.40-7.33 (m, 3H), 7.19-7.11 (m, 4H), 7.02 (dd, J=8.0, 1.7 Hz, 1H), 6.81 (td, J=6.0, 3.4 Hz, 2H), 6.73 (dd, J=8.0, 4.6 Hz, 1H), 3.73 (s, 3H), 2.81-2.73 (m, 2H), 2.62-2.55 (m, 2H), 2.28-2.19 (m, 1H), 2.02-1.92 (m, 1H); LCMS: 518 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[C:22]([F:35])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[C:22]([F:35])[CH:21]=1)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=512.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].[I:13]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C.O>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([I:13])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1C(=O)OC
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(C)c(I)c1C(=O)OC
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a flask, methyl 1-ethyl-3-methylpyrazol-5-ylcarboxylate (1.00 g, 0.006 mol, Ref. CN1626520A) was dissolved in 10 mL of DMF and N-iodosuccinimide (1.47 g, 0.007 mol) was added in batches. After reacting for 8 h at r.t., the mixture was diluted with 50 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:10 as eluent) gave 0.82 g of the title compound as a yellow oil (yield 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=O)[CH:8]=1)[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>C(O)(=O)CC>[CH2:1]([O:3][C:4]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:20]3[NH:16][C:17]([C:13]([C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=4)=[C:17]4[N:16]=[C:20]([C:13]([C:9]5[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=5)=[C:17]5[NH:16][C:20](=[C:13]([C:9]6[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=6)[C:17]6[CH:18]=[CH:19][C:20]=2[N:16]=6)[CH:19]=[CH:18]5)[CH:19]=[CH:18]4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)CCc1cccc(C=O)c1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: CCOC(=O)CCc1cccc(-c2c3nc(c(-c4cccc(CCC(=O)OCC)c4)c4ccc([nH]4)c(-c4cccc(CCC(=O)OCC)c4)c4nc(c(-c5cccc(CCC(=O)OCC)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
20.62 g (0.10 mol) of 3-{3-formylphenyl)-propionic acid ethyl ester (CARN 110114-05-1) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is slowly instilled and the dark solution is stirred for 1 hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After the drying of the organic phase on sodium sulfate, it is filtered and concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/ethanol. The residue of the product fractions that are concentrated by evaporation is recrystallized from isopropanol.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 3,4-methylenedioxyphenylacetic acid (4.2 g, 23 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.5 mL). The mixture was refluxed for 48 h, cooled to room temperature, and neutralized with saturated NaHCO3. The methanol was removed in vacuo. The residue was extracted with 1:1 hexane/EtOAc (2×100 mL). The combined organic phase was washed with water, saturated NaHCO3, and brine, and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as an oil (3.9 g, 86%). 1H NMR (CDCl3) 6.78-6.72 (m, 3H), 5.95 (s, 2H), 3.69 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C1C(=O)N([Br:18])C(=O)C1>C(Cl)Cl>[Br:18][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Br:1])[NH:8][CH:9]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Brc1ccnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol) and NBS (0.918 g, 5.16 mmol) in DCM (20.0 mL) was stirred at 0° C. for 1.5 hour. The resulting suspension was filtered, washed with DCM, residue collected, dried in a 50° C. oven overnight to afford the title compound (1.014 g). LCMS (A): m/z (M+H)+ 277, C7H4Br2N2 requires 276 (basic).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=2)=[CH:6][N:5]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: COCc1ccc(Oc2ccc([N+](=O)[O-])c(OC(C)C)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COCc1ccc(Oc2ccc(N)c(OC(C)C)c2)cn1
Yield: 74.2 %

Procedure:
A mixture of 2-(methoxymethyl)-5-[3-(1-methylethoxy)-4-nitrophenoxy]pyridine (20.5 g), iron (powder, 17.9 g), calcium chloride (710 mg), ethanol (400 mL) and water (100 mL) was refluxed for 5 h. The mixture was filtered with celite. The filtrate was concentrated in vacuo to remove ethanol. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by basic silica gel chromatography (ethyl acetate:hexane=5:95 to 1:3, volume ratio) to give the title compound (13.77 g, 74%) as a brown oil. MS 289 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[NH:4][C:3]1=[O:14].[CH2:16]1[C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)[NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:16]1[C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)[N:19]([C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:14])[C:2]3([CH3:1])[CH3:15])=[O:13])[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC1(C)C(=O)Nc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc21
Yield: 19 %

Procedure:
The title compound is prepared from 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.95 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Br)cc3)C2)c1

Procedure:
The compound of Example 22 was prepared according to the general preparation protocol A from 4-bromobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.28 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine
Reaction SMILES: [CH3:1][C:2]1[C:3](S(C)(=O)=O)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[OH:21][C:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Reactant: Oc1csc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of 0.8 g (2.6 mmol) of 5-methyl-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.44 g (2.6 mmol) of 3-hydroxy-5-trifluoromethylthiophene and 0.72 g (5.2 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.5 g of 5-methyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].S(OCC)(O[CH2:16][CH3:17])(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[C:3]=1[F:9]
Reactant: CCOS(=O)(=O)OCC
Reactant: Oc1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cccc(Cl)c1F
Reaction time: 0.5 h

Procedure:
The compound (b5) was added dropwise to a reactor having 1,200 g of a 10% sodium hydroxide aqueous solution placed therein over 30 minutes in a temperature range of 20 to 40° C. Thereafter, 462 g of diethyl sulfate was added dropwise thereto over 1 hour in a temperature range of 25 to 35° C., followed by stirring for 5 hours in that temperature range. The resulting organic layer was collected and washed with 200 mL of water in three times, followed by drying, to obtain 505 g of 1-chloro-3-ethoxy-2-fluorobenzene (b44). The resulting liquid was colorless.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[NH:33][C:32]2=[O:40])[CH2:27][CH2:26]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=6[NH:33][C:32]5=[O:40])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2n1C1CCN(Cc2ccc(-c3nc4ncccc4cc3-c3ccccc3)cc2)CC1

Procedure:
To a solution of 4-(3-phenyl-1,8-naphthyridin-2-yl)benzaldehyde (9-3) (135 mg, 0.44 mmole) in dry DMF (2 mL) was added 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (123 mg, 0.57 mmole) and HOAc (0.13 mL, 2.18 mmole) at RT. After 30 min NaBH(OAc)3 (120 mg, 0.57 mmole) was added. After 4 hr the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0–10% MeOH/CH2Cl2) gave the title compound as a cream colored solid (9-4): 1H-NMR (500 MHz, CDCl3) δ 9.15 (dd, J=1.71, 2.44 Hz, 1 H), 8.56 (bs, 1 H), 8.24 (m, 1 H), 8.19 (s, 1 H), 7.53 (m, 2 H), 7.30 (m, 7 H), 7.06 (m, 3H), 4.36 (m, 1 H), 3.56 (s, 2 H), 3.01 (d, J=11.47 Hz, 2 H), 2.44 (m, 2 H), 2.17 (m, 2H), 1.79 (d, J=11.72 Hz, 2 H); HRMS, calc'd for C33H29N5O (M+1), 512.2445; found 512.2478.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[C:4]#[N:5].[S:15](Cl)(=[O:18])(=[O:17])[NH2:16]>>[S:15](=[O:18])(=[O:17])([O:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:15](=[O:18])(=[O:17])[NH2:16])[C:3]=1[C:4]#[N:5])[NH2:16]
Reactant: N#Cc1c(N)cccc1OCCCO
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCOS(N)(=O)=O
Yield: 30 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(3-hydroxypropoxy)benzonitrile (Example 238b) and sulfamoyl chloride in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.11-2.14 (m, 2H), 4.16-4.21 (m, 4H), 6.96 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.26 (s, 2H), 7.49 (s, 2H), 7.56 (t, J=8.4 Hz, 1H), 9.46 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C(C)C)[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC(C)C)cc3s2)cc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cc3ccc(O)cc3s2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
2-(4-Methoxyphenyl)-6-isopropoxybenzo[b]thiophene (1.0 g, 3.35 mmol) was dissolved in 10 mL of methylene chloride and warmed to 30° C. Boron trichloride (3.685 mL, 3.685 mmol 1M in methylene chloride) was slowly added to the stirring reaction solution. The reaction was allowed to proceed for one hour at ambient temperature. The reaction was quenched with the dropwise addition of methanol (0.536 g, 16.75 mmol). The reaction was stirred for two hours and a white precipitate formed. The solid was filtered off, was hed three times with 10 mL portions of methylene chloride and dried to yield the title compound as a white solid. EA calculated for C15H12O2S: C, 70.29; H, 4.72; S, 12.51. Found: C, 67.69; H, 4.65; S, 12.02. MS(FD): m/e=256 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Br.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[O:12][CH3:11]
Reactant: C[O-]
Reactant: Cn1ncc(Br)c(Br)c1=O
Agent: [Na+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Br
Temperature: 23 °C
Reaction time: 3 h

Procedure:
4,5-Dibromo-2-methyl-3(2H)-pyridazinone (20 g, Maybridge Chemical Company) was cooled in an ice bath and treated successively with methanol (200 mL) and sodium methoxide (12 mL of a 30% solution in methanol). The ice bath was removed and the reaction was allowed to stir at 23° C. for 3 h. The methanol was removed by evaporation at reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated to provide the desired product 17 g as a whim solid melting at 146°-147° C. 1 H NMR (CDCl3): 7.7 (1H), 4.0 (3H), 3.8 (3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Cc1ccc(-c2ccoc2)cc1N
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)CSCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-([5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18](Cl)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>CN1CCCC1=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([F:26])=[C:28]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Cl)nc12
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 130 °C

Procedure:
To a solution of N-(4-fluorophenyl)-2-chloro-4-hydroxy-6-nitroquinazoline-8-carboxamide (0.050 g) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (0.053 mL). The reaction mixture was heated at 130° C. for 4.5 h, then cooled to room temperature and diluted with water. The resulting mixture was cooled at 5° C. for 3 h and the precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a grey solid (0.054 g). 1H NMR (300 MHz, DMSO-d6): 12.31 (s, 1H), 11.87 (s, 1H), 9.64 (s, 1H), 9.00 (d, J=2.9 Hz, 1H), 8.8. (d, J=2.9 Hz, 1H), 7.95-7.87 (m, 2H), 7.39-7.32 (m, 1H), 7.15-6.95 (m, 4H); HPLC (Method E): 4.3 min.; MS (APCI−): m/z 504.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](O)([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].[F:15]C(F)=C>>[F:1][C:2]([F:14])([F:13])[C:3]([F:15])([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(CC(F)F)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)F
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,4,4-pentafluoro-2-butanol may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,4,4-pentafluoro-2-butanol.