Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CN1CCCC1c1cncc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C#Cc1cncc(C2CCCN2C)c1

Procedure:
Repeating the procedure of Example 16, but using trimethylsilylacetylene in place of phenylacetylene, 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine and the fumarate derivative thereof were obtained as follows. 5-Trimethylsilylethyny-3-(1-methyl-2-pyrrolidinyl) pyridine (516 mg, 2 mmol) and cesium carbonate (200 mg, 0.6 mmol) were dissolved in methanol (10 mL) and heated under reflux for 5 h. After cooling the solvents were removed in vacuo and the residue dissolved in ethyl acetate (40 mL) and washed with water (10 mL). The aqueous layer was extracted with ethyl acetate (40 mL) and the combined organic extracts washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed on "flash" silica gel with ethyl acetate: hexane (1:9, 1:4, 1,3) to afford 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 218 mg, 59%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:34])([CH3:33])[CH2:19][N:20]1[C:28]2[C:23](=[C:24]([CH2:30][CH2:31][CH3:32])[C:25]([OH:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][C:18]([CH3:33])([CH3:34])[CH2:19][N:20]1[C:28]2[C:23](=[C:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: COC(=O)c1ccc(OCCCCBr)cc1
Reactant: CCCc1c(O)ccc2c1ccn2CC(C)(C)C
Product: CCCc1c(OCCCCOc2ccc(C(=O)O)cc2)ccc2c1ccn2CC(C)(C)C

Procedure:
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 7.92 (d, 2H), 7.24 (d, 1H), 7.20 (s, 1H), 7.02 (d, 2H), 6.87 (d, 1H), 6.37 (d, 1H), 4.14 (t, 2H), 4.01 (t, 2H), 3.90 (s, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.92 (s, 9H), 0.90 (t, 3H). MS (ESI): 438 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:35])=[C:23]([C:25]4[O:26][C:27]5[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=5[C:29]=4[Cl:30])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:37].Cl.CCOCC>>[ClH:30].[ClH:37].[Cl:30][C:29]1[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[O:26][C:25]=1[C:23]1[C:22]([NH2:35])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:18]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4oc5ccccc5c4Cl)c3)cn2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1oc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
To a solution of 4-{4-[6-Amino-5-(3-chlorobenzofuran-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (78.0 mg, 0.158 mmol) in DCM (2.5 mL, 39 mmol) was added 1.0 M of HCl in Et2O (1.5 mL; 1.5 mmol), and the mixture was stirred at ambient temperature for 8.5 h. The solid formed was filtered off, washed with DCM, and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.20-9.09 (brm, 1H), 9.02-8.91 (brm, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.96 (very brs, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.74 (dd, J=8.4, 0.8 Hz, 1H), 7.55 (ddd, J=1.2, 7.2, 8.4 Hz, 1H), 7.48 (ddd, J=0.8, 7.2, 8.4 Hz, 1H), 4.55-4.46 (mc, 1H), 3.38 (brd, J=12.8 Hz, 2H), 3.08 (q, J=12.2 Hz, 2H), 2.26-2.08 (m, 4H). MS(ES+): m/z=394.10/396.09 (65/21) [MH+], 311.04/313.07 (100/34) [MH+-piperidine]. HPLC: tR=2.28 min (polar—5 min, ZQ3).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]=[O:14])[CH:7]=1.[CH:15]1([Mg]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O1CCCC1.O>O1CCCC1>[CH:15]1([CH:13]([C:8]2[CH:7]=[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)[S:10][C:9]=2[CH2:11][CH3:12])[OH:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCc1sc(C2OCCO2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1sc(C2OCCO2)cc1C(O)C1CCCCC1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-2-ethylthiophene-3-carbaldehyde (6.36 g) synthesized above in tetrahydrofuran (130 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (40 mL) at 0° C., and the mixture was stirred for 1.5 hr under an argon atmosphere. Water was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (6.30 g, 71%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][N:21]([CH3:30])[C:20]1=[O:31]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][CH2:22][N:21]([CH3:30])[C:20]2=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1CCc2ccccc2C(N)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)CCc2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.15 in ethyl acetate) and purification was by flash chromatography using ethyl acetate as the eluant.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17](OC)=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ncccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Temperature: -72 °C

Procedure:
Under argon 12.3 g (41.7 mmol) of dimethyl 1-(3-chloropyridin-2-yl)-1H-pyrazole-3,5-dicarboxylate are introduced in 430 ml of tetrahydrofuran and this initial charge is cooled to −72° C. and admixed dropwise with 100 ml (100 mmol of a 1 M solution in hexane) of diisobutylaluminium hydride. The mixture is allowed to warm to 0° C. overnight and 65 ml of water are cautiously added. The solvents are removed on a rotary evaporator and the residue is extracted to exhaustion with methanol on a Soxhlet apparatus. Following removal of the solvent, the residue is purified on silica gel (cyclohexane/ethyl acetate=2:1→1:1).
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:2].[H-].[Na+].C(O)C[OH:29]>>[C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH2:18][OH:29])=[O:15])[C:4]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:2]
Reactant: OCCO
Reactant: CCOC(=O)c1c(N2CCCCC2)c(C#N)c(=O)n2ccccc12
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)c(C(=O)OCCO)c2ccccn2c1=O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a solution of 1.10 g of 3-cyano-1-ethoxycarbonyl-2-piperidino-4H-quinolizin-4-one (Example 6, S-35) in 30 ml of ethylene glycol was added 150 mg of 60% sodium hydride, and the reaction mixture was stirred at 100° C. for 14 hours. After cooling, the precipitated crystals were collected by filtration and then the crude crystals were chromatographed on a silica gel column using a mixed solvent of dichloromethane and diethyl ether (1:1) as an eluent to obtain 180 mg of 3-cyano-1-(2-hydroxyethoxycarbonyl)-2-piperidino-4H-quinolizin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Reactant: COc1ccccc1B(O)O
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2OC)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (50 g, 0.135 mmol) in a mixture of tetrahydrofuran (10.5 mL) and water (2.5 mL) was added 2-methoxyphenylboronic acid (24.5 mg, 0.162 mmol) and cesium carbonate (175.3 mg, 0.54 mmol). The solution was then degassed by bubbling a flux of argon for 20 minutes before adding tetrakis(triphenylphosphine)palladium (4.24 mg, 0.0034 mmol). The reaction mixture was then stirred overnight at 80° C. under argon atmosphere before allowing to cool down to room temperature and diluting with ethyl acetate. The reaction mixture was then filtered; the filtrate was then washed twice with water and dried over sodium sulfate before being concentrated in vacuo. The residue was then purified by column chromatography (SiO2, EtOAc/Heptane, 0-60%) to yield the title compound as a light yellow solid (42.5 mg, 79%).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:12][O:13][CH3:14])[NH:10][CH:11]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:14][O:13][CH2:12][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[CH:11][N:10]=1
Reactant: COCc1nc(C=NNC(=S)SC)c[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCc1ncc2cn[nH]c(=S)n12

Procedure:
A miture of 62.4 gm. of 3 -[2-(methoxymethyl)-4-imidazolyl]methylene dithiocarbazic acid methyl ester and 250 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 219.5°-223° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=2)[CH:30]=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][C:2]([C:3]([NH2:5])=[O:4])=[CH:30][C:29]=3[CH:32]=2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cc(N2CCN(Cc3ccccc3)CC2)ccc1O
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: NC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
10 ml of 1-methyl-2-pyrrolidone, 0.4 g of chloroacetamide and 0.8 g of potassium carbonate are added at 20° C. with stirring/under nitrogen to 1.0 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde. The mixture is stirred at 60° C. for 16 hours, cooled and then filtered, and the solvent is removed under reduced pressure. The residue is taken up in MTB ether, re-filtered and concentrated, and the residue is crystallized from toluene. The isolated yield is 0.73 g (65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1coc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(OCc2nc(C(=O)O)co2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a stirred solution of methyl 2-[[3-[(S)-(tert-butoxycarbonylamino)-phenyl-methyl]phenoxy]methyl]oxazole-4-carboxylate (0.8 g, 1.825 mmol) in THF (9.2 mL) and methanol (9.2 mL) was added a solution of lithium hydroxide monohydrate (153.1 mg, 3.65 mmol) in water (3.6 mL). The reaction was stirred at room temperature for 18 h. The majority of the solvent was removed in vacuo. The residue was diluted with water (50 mL) and cooled to 0° C. 2N aqueous HCl (1.82 mL) was added dropwise. The reaction mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a colourless solid (736 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:36]=[C:24]2[N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:37])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:36]=[C:24]3[NH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:37])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]([Mg]Cl)([CH3:15])[CH3:14].C(Br)C=C.C([Cu])#N>C1COCC1>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH2:15][CH:13]=[CH2:14])[CH:3]=1)[CH3:9]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CC(C)[Mg]Cl
Agent: N#C[Cu]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1cccc(C(=O)OCC)c1
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A −45° C. solution of ethyl 3-iodobenzoate (2.434 g, 8.8 mmol) in 40 mL THF was treated with i-PrMgCl (4.8 mL, 9.6 mmol, 2 M/ether). After 1 h, allyl bromide (1.6 mL, 18.9 mmol) was added followed by CuCN (79 mg, 0.88 mmol). The reaction was stirred for 1 h and then was quenched by addition of 50 mL saturated NH4Cl solution. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (5% ethyl acetate/hexanes→10%) gave compound 7 (1.145 g, 68%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].S(Cl)([Cl:25])(=O)=O>ClCCl.O>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(Cl)cc1
Yield: 68.1 %

Procedure:
A solution of (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (500 mg) in dichloromethane was cooled to 0° C., and sulfuryl chloride (285 mg) was dropwise added thereto. The resultant mixture was stirred at the same temperature for 2 hours, diluted with water and extracted with diethyl ether. The solvent was dried and removed, and the residue was subjected to HPLC with a mixture of hexane and ethyl acetate to give 382 mg of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](=[O:31])[CH2:29]Br>CN(C=O)C>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](=[O:31])[CH2:29][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: O=C(CBr)c1cc2ccccc2o1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (460.5 mg) in DMF (5 mL) was added sodium hydride (103 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 1-(1-benzofuran-2-yl)-2-bromoethan-1-one (633 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C@H:5]1[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7][C@@H:6]1[OH:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[OH:28][C@@H:6]1[C@@H:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:24][C@@:23]2([CH3:25])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:26])[CH2:20][C@@:19]2([CH3:27])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1
Reactant: C1COCCN1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β(2'-Chloroethoxy)-3α-hydroxy-5α-pregnane-11,20-dione (100 mg.) was dissolved in morpholine (10 ml.) and the solution heated on a steam-bath for 24 hours, complete reaction occurring. The morpholine was evaporated off in vacuo and the orange oil obtained purified by preparative TLC in ethyl acetate to give the title compound (40 mg.) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][P:23](=[O:27])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
1-(Chloromethyl)-3-(4-(trifluoromethyl)phenoxy)benzene (1.3 g, 4.5 mmol) was treated neat with triethylphosphite (1.2 mL, 6.8 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (0-30%, EtOAc:CH2Cl2) to afford the title compound (1.76 g) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:16][N:17]([CH3:18])[CH3:19]
Reactant: N#CCC(=O)Nc1ccccc1Br
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1Br

Procedure:
As for Example 1, 2'-bromo-2-cyanoacetanilide, white crystals, m.p. 140°-141° C. (prepared as described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-bromo-2-cyano-3-dimethylaminoacrylanilide as off-white prisms, m.p. 91°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].CO.[Cl:14][C:15](Cl)=[CH:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(Cl)Cl>[Cl:14][CH:15]=[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)C=C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=CCl)Oc1ccc(Cl)cc1
Yield: 81.6 %

Procedure:
26 g (0.2 mol) of p-chlorophenol were reacted with 40 ml of 30% strength sodium methylate solution (0.2 mol) in 150 ml of dimethylformamide. After the methanol had been stripped off, a further 50 ml of dimethylformamide were distilled off under 20 mbar. 15.3 g (0.1 mol) of 1,1-dichloro-3,3-dimethyl-1-butene were then added and the mixture was heated under reflux for 18 hours. The solution was diluted with methylene chloride and extracted three times by shaking with dilute sodium hydroxide solution. The organic phase was dried over sodium sulphate and the solvent was removed in vacuo. Distillation gave dimethylformamide in the first runnings, and 20 g of 1-chloro-3,3-dimethyl-2-(4'-chlorophenoxy)-1-butene, that is to say 81% of theory, as the main fraction at boiling point 110°-128° C./0.15 mm Hg. NMR (CDCl3): δ 1.15 (s, 9H), 5.9 (s, 1H) and 6.8- 7.4 (m, 4H). ##STR9##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]([NH:8][S@](C(C)(C)C)=O)[CH3:7].[ClH:15]>CO>[ClH:15].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]([NH2:8])[CH3:7]
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccco1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccco1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 124.2 %

Procedure:
In a round-bottomed flask, (S)-2-methyl-propane-2-sulfinic acid ((R)-1-furan-2-yl-ethyl)-amide (514 mg, 2.27 mmol) was dissolved in methanol 4 ml) and hydrogen chloride (4.0 M in 1,4-dioxane, 1.2 ml, 4.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 15 min then concentrated to give 416 mg of (R)-1-furan-2-yl-ethylamine hydrochloride as a dark brown waxy solid which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][C:37]=1[O:54][CH3:55])#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:37]([O:54][CH3:55])[CH:38]=4)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 67.7 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.30 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) and ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate (0.26 g) in diethylaniline (2 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.25 g, 70%).