Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1.[CH2:28](S)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][CH3:28])=[O:22])=[CH:4][CH:3]=1
Reactant: CCS
Reactant: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.05 g (2.7 mmol) of 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (EP 166,591, Example 22) and 800 μL of ethanethiol (10 mmol) in 20 mL of CH2Cl2 at -20° C. was added in portions 2.17 g (16 mmol) of AlCl3. The reaction turned light orange and was stirred at room temperature overnight. In the morning, the reaction was completed (tlc) and it was poured into a solution of 1N HCl and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and filtered. The filtrate was evaporated and to the residual syrup (680 mg) was added 20 mL of Et2O followed by an ethereal solution of diazomethane. Evaporation of the solvent left the crude title compound which was used without further purification.
Reaction SMILES: [OH-].[Li+].[C:3]1([C:9]2[N:10]=[C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19]([O:21]C)=[O:20])[CH2:15]3)[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[C:3]1([C:9]2[N:10]=[C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15]3)[S:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Lithium hydroxide (10 mg, 0.39 mmol) was added to a solution of methyl 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylate (75 mg, 0.26 mmol) in THF-H2O (3 mL, 7:3 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature, stirred for 1 h, concentrated under reduced pressure, and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to ˜3 using 1.5N HCl and the organic product was extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylic acid (40 mg, yield 56%) as off-white solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C14H14N2O2S: 274.08. found: 275.0 (M+H)+
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([F:22])([F:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[OH:24][CH:25]1[CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:26]1>>[F:21][C:12]([F:22])([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]2[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:26][CH:25]2[OH:24])=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)COc2ccccc2)cc1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCC(F)(F)COc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method G, 0.350 g of 2,2-difluoro-3-phenoxypropyl toluene-4-sulphonate and 0.452 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1 carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: [Mo:1]=[O:2].O.O.O.O.O.[N+]([O-])([O-])=[O:9].[Bi+3:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=[O:18]>O.[OH-].[NH4+].[N+]([O-])(O)=O>[O-2:9].[O-2:14].[O-2:18].[O-2:2].[O-2:9].[O-2:9].[O-2:9].[O-2:9].[O-2:9].[Mo:1].[Mo:1].[Bi+3:12].[Bi+3:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=[Mo]
Agent: [Bi+3]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: [Mo]
Product: [O-2]
Reaction time: 3 h

Procedure:
28.78 grams of molybdenum oxide (MoO3) were dissolved in a mixture of 72 ml of water and 36 ml of concentrated ammonium hydroxide, added to a solution of 97 grams of bismuth nitrate pentahydrate in ~184 ml of water and 30 ml of concentrated nitric acid with stirring, and the pH of the resulting mixture was adjusted to between 3 and 6.5 using ammonium hydroxide whereafter it was boiled for approximately 3 hours. The precipitate was filtered and washed with approximately 1000 ml of water.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:11]([CH2:13][C:14](O)=[O:15])#[N:12]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:13]([C:11]#[N:12])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Cl)ccc1CO
Product: N#Cc1cc2ccc(Cl)cc2[nH]c1=O
Yield: 16 %

Procedure:
2-Amino-4-chlorobenzyl alcohol (3 g, 19.29 mmol) and cyanoacetic acid (3.61 g, 42.44 mmol) were reacted in a similar manner as described in Example 1 to give 0.63 g of 7-chloro-3-cyano-2(1H)-quinolone. mp 306°-309° C. This nitrile (0.46 g) was dissolved in 1-methylpyrrolidinone and treated with triethylammonium hydrochloride (0.465 g) and sodium azide (0.44 g). The reaction was heated to 140° C. for 1 h, cooled, acidified (HCl), and extracted with ethyl acetate (2×). The combined organic phases were extracted into dilute sodium hydroxide (2×) and washed with diethyl ether. The aqueous layer was acidified and the precipitate which formed was extracted into ethyl acetate (3×). The combined organic phases were washed with water and then evaporated to give the title compound as a powdered brown solid; mp 327° C. (dec) (DMF, acetone, water). (Found: C, 48.61; H, 2.47.C10H6ClN5O requires C, 48.50; H, 2.44%); δH (360 MHz, DMSO-d6) 7.36 (1H, d, dd, J=8.4 and 2.0 Hz, 6-H), 7.44 (1H, d, J=2.0 Hz), 8.01 (1H, d, J=8.4 Hz, 5-H), 8.98 (1H, s, 4-H), 12.3-12.7 (1H, vbr s, NH); m/z (EI+) 247 (M+).
Reaction SMILES: [ClH:1].C([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14])(=O)C.Cl.[OH-].[Na+]>>[ClH:1].[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[CH3:14]
Reactant: CCOc1ccccc1N(CC1CNCCO1)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1NCC1CNCCO1
Temperature: 0 °C

Procedure:
A mixture of 2-(N-acetyl-2-ethoxyanilino)methylmorpholine hydrochloride (2 g.) and concentrated hydrochloric acid is heated under reflux for 24 hours. The solution is cooled, diluted with ice (25 g.), basified with sodium hydroxide solution and extracted with ether (2 × 100 ml.). The ether extract is dried (Na2SO4) and treated with ethereal HCl to give 2-(2-ethoxyanilino)methylmorpholine hydrochloride, m.p. 180°-181°C. on recrystallisation from ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][C@@H:13]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[C:24]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:18]([O:17][C:16](=[O:21])[NH:15][C@@H:13]1[CH2:12][C:7]2[N:8]([CH2:29][C:25]3[C:24]([O:31][CH3:32])=[C:23]([Cl:22])[CH:28]=[CH:27][N:26]=3)[C:9]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[CH2:14]1)([CH3:19])[CH3:20]
Reactant: COc1c(Cl)ccnc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Cl)ccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of (S)-isopropyl 7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamate (680 mg, 2.40 mmol) and 4-chloro-2-(chloromethyl)-3-methoxypyridine (553 mg, 2.88 mmol) in dimethylformamide (5 mL) is added cesium carbonate (1.17 g, 3.60 mmol) and the mixture stirred at room temperature overnight. The reaction mixture is diluted with water and the beige solid is filtered. It is rinsed with water and then dried in a vacuum oven at 50° C. for 48 h to obtain a gray solid (970 mg, 92%). LC-ES/MS m/z 439.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2>>[OH:44][C@H:29]([CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:26])[CH3:1])=[N:10][C:9]3=[O:11])=[CH:18][CH:17]=2)[CH2:20][CH2:21]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Intermediate 12) according to the procedure of Example 1 as a yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 6 H), 2.40 (t, J=7.9 Hz, 2 H), 2.55-3.20 (m, 12 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 7.00 (d, J=8.9 Hz, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H), 8.82 (brs, 1 H); MS (ES) m/z: 304.6 ((M+2H)2+, 100%); 608.1 (MH+, 10%); HRMS Calcd. for C30H38N7O5S (MH+): 608.2655. Found: 608.2655.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[CH2:32]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([C:38]1[CH:37]=[CH:36][C:35]([CH:33]2[CH2:32][N:31]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([C:16]4[N:15]=[C:14]([CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)[NH:18][C:17]=4[CH3:19])[CH:21]=3)=[O:24])[CH2:34]2)=[CH:42][CH:41]=1)#[N:40]
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 μL, 5.08 mmol) in DMF (25 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (3×10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title compound as a foam. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [F-:1].[Na+].C(#N)C.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(C[O:18][CH3:19])OC>>[F:1][C:19]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:18]
Reactant: OCc1ccccc1
Reactant: COCCOC
Reactant: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)OCc1ccccc1

Procedure:
The process is performed as in Example 1 with, in the first reactor, 168 g (4 mol) of sodium fluoride powder having the same characteristics as described in Example 1 and 320 ml of acetonitrile and, in the second reactor, 108 g (1 mol) of benzyl alcohol, 50.5 g (1.2 mol) of sodium fluoride of the same characteristics as above and 150 g of dimethoxyethane.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:16]1([CH3:27])[CH:21]=[CH:20][C:19]([S:22]([O:25]C)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH3:27])[CH:17]=[CH:18][C:19]([S:22]([O-:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1.[C:1]([NH:4][C:5]1[N:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH:11]=[N+:12]2[CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(C)ccnc2n1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(C)cc[n+](C)c2n1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
7-Acetamido-4-methyl-1,8-naphthyridine (13.3 g., 0.066 mole) was refluxed for 8 hours with 12.7 g. of methyl p-toluenesulfonate in 150 ml. of dry acetonitrile. The dark purple solution was cooled at 5° for several days; 21.8 g. (85%) of felted needles, m.p. 200°-202°, was removed. Addition of a large volume of ether to the mother liquors precipitated 2.3 g. (9%) more of the salt; m.p. 185°-190°. The 1H nmr was consistent with that expected for the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:14]([O-])([O-])=O.[K+].[K+].CO[CH2:22][CH2:23]OC>O.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>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH:22]=[CH2:23])[CH:3]=[CH:4][N:5]=2)[N:10]=1)[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Product: C=Cc1ccnc2ccc(OCC)nc12
Temperature: 85 °C

Procedure:
A suspension of 8-bromo-2-methoxy-[1,5]naphthyridine (1.2 g, 5 mmol), tetrakis(triphenylphosphine)palladium (0.29 g), K2CO3 (0.691 g) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (1.2 g, prepared according to J. Org. Chem. (2002), 67, 4969) in DME (40 mL) and water (12 mL) was heated at 85° C. under N2 overnight. The mixture was cooled to rt, diluted with water and extracted with ether. The combined org. extracts were dried over MgSO4 and concentrated in vacuo. The product (1 g of red oil) was used as such without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[OH-].[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:14]=23)=[C:4]([F:9])[CH:3]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Oc1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnc2c(sc3ccccc32)c1Oc1ccc(Cl)cc1F
Yield: 55 %

Procedure:
A mixture of 0.59 mL (5.5 mmol) of 4-chloro-2-fluorophenol and 100 mg (1.78 mmol) of potassium hydroxide is heated until a homogeneous solution is formed. To this is added 245 mg (1.00 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and the mixture is heated for 2 hours. Ethyl acetate is added and the solution is washed with 1 N NaOH. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The solid is collected and recrystallized from ethyl acetate to give 195 mg (55%) of a light beige solid, mp 174–175° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15](OC)=[O:16])[N+:11]([O-:19])=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:9]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[OH-].[Na+]>O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[N:11]3[O:19][C:15](=[O:16])[N:14]=[C:12]3[N:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Nc1cc(N2CCC(O)CC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCC(O)CC2)nc2nc(=O)on12
Reaction time: 3.5 h

Procedure:
3.1 G. of dimethyl racemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 100 ml. of methylene chloride and 100 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.6 and stirred at this pH for 3.5 hours. The two phases are then separated and the aqueous phase is adjusted to pH 3.2 with concentrated hydrochloric acid solution. The separated white precipitate is filtered off, pre-dried and recrystallized from methylene chloride and methanol, there being obtained pure methyl racemic-5-(4-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 250°-260° C. (decomposition).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]#[N:14])[CH3:4].[CH2:20](Br)[Br:21].CCOCC>CN(C)C=O.O>[Br:21][CH2:20][C:12]([C:13]#[N:14])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:3][CH3:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: BrCBr
Reactant: CCCCCC(C#N)c1ccccc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCCCC(C#N)(CBr)c1ccccc1OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A 200 ml three-neck flask fitted with a reflux condenser, nitrogen inlet, thermometer and addition funnel was charged with 1.8 grams (0.045 moles, 1.28 ec.) of 60% NaH, washed 2×40 ml of hexane, in 30 ml of dimethyl formamide (DMF). While stirring at room temperature, 1.41 grams of 35% KH (with removal of the mineral oil before washing with hexane, assumed 100% KH, 0.035 moles, 1.0 ec.) in 20 ml of DMF was added. To the reaction was added 8.10 grams (0.0350 moles, 1.0 ec.) of 2-(2-ethoxyphenyl)heptanenitrile in 25 ml of DMF. After stirring at room temperature for 1 hour, 9.15 grams (0.0525 moles, 1.5 eg.) of CH2Br2 in 25 ml of DMF was added dropwise over 10 minutes. The reaction exothermed slightly and was stirred at room temperature overnight after which GLC indicated the reaction was 80% product. An additional 0.7 g of 100% KH (0.5 ec.) was added in 20 ml of DMF, after washing with 20 ml of hexane, and this was followed by an additional 3.0 grams of CH2Br2The reaction was stirred for an additional 3 hours and was complete by GLC. Workup with ether and water gave after concentration 10.97 grams of a thick oil (97.2% yield) which was used directly in the coupling procedure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[I-].[K+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][N:19]([CH2:35]/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: ClC/C=C/c1ccccc1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(C/C=C/c2ccccc2)CC1
Reaction time: 4.5 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxo-1,2-dihydroquinolin-1-yl)propyl)piperidine-4-carboxylate, 0.11 g of potassium carbonate, 41 μL of ((1E)-3-chloro-1-propenyl)benzene and 45 mg of potassium iodide were added at room temperature and stirred for 4.5 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=35:1], to give 0.11 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-((2E)-3-phenyl-2-propen-1-yl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([N:8]([CH2:21][CH2:22][C:23]#[CH:24])[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:25]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1I)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[C:4]([O:3][C:1]([N:8]([CH2:21][CH2:22][C:23]#[C:24][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[NH:38][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(=[O:11])=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reactant: C#CCCN(C(=O)OC(C)(C)C)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1)S(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 93.8 %

Procedure:
A warm (45° C.) solution of N-BOC-N-but-3-ynyl-(3,4-dichloro-phenyl)-methanesulfonamide (347 g, 0.885 mol), dichlorobis(triphenylphosphine)palladium (II) (3.50 g, 4.99 mmol), and DMF (700 mL) was added slowly over 8 h to a warm (55° C.), stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (350 g, 0.833 mol), dichlorobis(triphenylphosphine)palladium (II) (3.5 g, 4.99 mmol), copper (I) iodide (20.0 g, 0.105 mol), triethylamine, (259 g, 2.56 mol), and DMF (250 mL). The reaction mixture was stirred and maintained at 55° C. for 30 m after complete addition. The reaction mixture was distilled at reduced pressure using a heating bath temperature of 40-45° C. to remove triethylamine. The reaction mixture was filtered through a celite pad. The pad was washed with DMF (40 mL). 2-Propanol (280 mL) was added to the filtrate. The mixture was warmed to 55° C. Water (280 mL) was added slowly over 1 h to the stirred mixture. The stirred mixture was maintained at 55° C. for 30 m after complete water addition. The mixture was cooled to 10° C. The solid product was collected by filtration and washed with cold 1/1 (v/v) IPA/water (2×300 mL). The solid was vacuum dried at <50° C. to give N-t-butoxycarbonyl-N{4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-C-(3,4-dichlorophenyl)-methanesulfonamide (534.5 g, 94%) with 98% purity (as determined by HPLC).