Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:14][C:15](O)=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH2:18][NH:19][C:20]([NH2:22])=[S:21].C(=O)([O-])[O-].[Na+].[Na+]>>[N:8]1([CH2:14][C:15]2[S:21][C:20]([NH2:22])=[N:19][N:18]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(O)CN1CCOCC1
Reactant: NNC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CN2CCOCC2)s1
Yield: 27.3 %

Procedure:
(4-Morpholinyl)acetic acid trifluoroacetic acid salt (1.0 g) and thiosemicarbazide (0.25 g) are heated in polyphosphoric acid (2.0 g) at 70° C. for 1 h. The mixture is cooled to room temperature and basified with sodium carbonate, which is extracted with CH2Cl2. The organic layer is dried (MgSO4), concentrated, and the residue is chromatographed (CH2Cl2/methanol, 9/1) to give 150 mg of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 201 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[Cl:18].[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Cl:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH:1][C:26]([C:23]1[C:22](=[O:29])[N:21]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:20]([CH3:19])[C:24]=1[CH3:25])=[O:27])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a suspension of 4-(4-amino-3-chlorophenoxy)picolinamide (191 mg, 0.72 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) in DCM (10 mL) was added EDCI (166 mg, 0.86 mmol) and HOAT (20 mg, 0.14 mmol). The reaction was stirred at 46° C. for 6 hours, followed by the addition of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.14 mmol) and EDCI (27 mg, 0.14 mmol). The mixture was further stirred at 46° C. for 13 hours, then cooled to rt and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (10 mL×3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (160 mg, 46.5%).
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30][N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Yield: 47 %

Procedure:
DCM (33 L) and N-methylpiperazine (21.45 L, 193.4 mol) were stirred at 25° C. and the solution from step 8 added over a minimum of 30 mins such that temperature 20-30° C. After stirring the solution for a further 30 mins water (55 L) was added and the organic phase was washed with water (2×55 L). The product was extracted into 0.8M HCl (66 L) and the layers separated. The aqueous phase was washed with DCM (55 L) and then basified with 2M NaOH to pH 10-11 and the product was extracted into EtOAc (2×55 L). The combined organic phase were filtered to remove solids and the evaporated followed by azeotroping with toluene and drying to constant weight to give the title compound, 6.63 kg (47% yield, 98% pure by hplc).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 0.19 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.19 g of potassium carbonate and 3 ml of methanol was heated under reflux for 27 hours. To this mixture was added 93 mg of potassium carbonate, and the mixture was further heated under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-methoxy-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 9”).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl-].[C:51]([NH:55][NH3+:56])([CH3:54])([CH3:53])[CH3:52]>C(#N)C>[C:51]([NH:55][NH:56][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)N[NH3+]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NNC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a suspension of (1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1.211 g, 5.0 mmol) and HATU (2.091 g, 5.50 mmol) in acetonitrile (100 mL) was added triethylamine (1.771 g, 17.50 mmol) at room temperature. 2-tert-Butylhydrazinium chloride (0.748 g, 6.00 mmol) was added to the solution and the reaction was stirred for 12 at room temperature. The mixture was concentrated. The residue was diluted with EtOAc (150 mL) and washed with NaHCO3 solution (100 mL). The organic layer was concentrated and purified by silica gel column chromatography to give the title compound (1.42 g) as a glassy solid. LCMS m/z=313.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.49 (dd, J=8.0 and 4.7 Hz, 1H), 1.18 (s, 9H), 1.24-1.29 (m, 1H), 2.29-2.34 (m, 1H), 2.75-2.80 (m, 1H), 2.94 (d, J=16.9 Hz, 1H), 3.03 (dd, J=16.5 and 6.2 Hz, 1H), 4.75 (bs, NH, 1H), 805 (bs, NH, 1H), 8.41 (dd, J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15].[CH3:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)[CH:23]=[C:22]([CH3:38])[C:21]=1O>ClCCl>[O:15]=[C:14]([CH3:16])[C:13]([O:18][C:21]1[C:22]([CH3:38])=[CH:23][C:24]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:28]=2)=[CH:25][C:20]=1[CH3:19])=[O:17]
Reactant: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1O
Reactant: CC(=O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(=O)C(=O)Oc1c(C)cc(Nc2ccn(-c3ccccc3)n2)cc1C
Reaction time: 16 h

Procedure:
1,1'-carbonyldiimidazole (4.9 g) was added batchwise to pyruvic acid (2.6 g) in dichloromethane (100 ml), and after 0.5 hours 2,6-dimethyl-4-(1-phenyl-1H-pyrazol-3-yl) aminophenol (2.8 g) was added. The mixture was left for 16 hours, then evaporated, and the residue was chromatographed (silica, dichloromethane) to give, after crystallisation (hexane/ethyl acetate), the title product (1.0 g) mp 123°-125°.
Reaction SMILES: N1C=CN=N1.[Na].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([O:16][CH2:17][CH2:18][S:12][C:9]1[N:10]=[CH:11][NH:7][N:8]=1)[CH3:14]
Reactant: Sc1nc[nH]n1
Reactant: CCOCCBr
Agent: [Na]
Agent: c1c[nH]nn1
Solvent: CCO
Product: CCOCCSc1nc[nH]n1

Procedure:
The novel intermediate triazole compounds used in the above preparation were prepared as follows. To a solution of 11.8 g. sodium in 350 ml. absolute ethanol was added 52.5 g. 1,2,4-triazole-3-thiol. To the resulting solution was added 84 g. 1-bromo-2-ethoxyethane and the resulting solution refluxed for 3 hours. The cooled reaction mixture was filtered, the filtrate was evaporated under reduced pressure to remove solvent, and the residue was dissolved in ether. The resulting solution was filtered, the filtrate was evaporated to remove solvent and the residue distilled under reduced pressure to give 3-(2-ethoxyethylthio)-1,2,4-triazole, b.p. 137°-145°C./0.3-0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][N:2]([CH2:4]Cl)[CH3:3].CN(CCCCl)C.C([N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)(=O)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:4][N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)[CH3:3]
Reactant: Cc1cc2n(C(=O)c3ccccc3)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1
Reactant: CN(C)CCl
Agent: CN(C)CCCCl
Product: Cc1cc2n(CN(C)C)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1

Procedure:
By substituting dimethylaminomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and utilizing 2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one product of Example 15 instead of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one, 4-dimethylaminomethyl-2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: C1OC1.P(Cl)(Cl)Cl.[Cl:8][CH2:9][CH2:10]O.[P:12]([O:21][CH2:22][CH2:23][Cl:24])([O:17][CH2:18][CH2:19][Cl:20])[O:13]CCCl.C(O)(=O)C=C.COC1C=CC(O)=CC=1>>[Cl:8][CH2:9][CH2:10][P:12](=[O:13])([O:17][CH2:18][CH2:19][Cl:20])[O:21][CH2:22][CH2:23][Cl:24]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: OCCCl
Agent: C=CC(=O)O
Agent: COc1ccc(O)cc1
Solvent: ClP(Cl)Cl
Solvent: C1CO1
Product: O=P(CCCl)(OCCCl)OCCCl
Reaction time: 3.25 h

Procedure:
Ethylene oxide, 816 g. (18.5 m) is added subsurface to a stirred solution of 824 g. (6.0 m) of phosphorus trichloride and 8.2 g. of 2-chloroethanol in 2.75 hr with cooling at 15°-20° C. The resulting reaction mixture consists of about 90% tris(2-chloroethyl) phosphite, the remainder being a mixture of phosphonates, is warmed to 80°, and 389 g. (5.4 m.) of acrylic acid containing 100 ppm of hydroquinone monomethyl ether is added in 1.2 hr with cooling at 80°-85°. The reaction mixture is warmed to 130° in 0.5 hr and kept at 130°-140° for 3.25 hr. Stripping to 165°/1 mm leaves 1881 g. of yellow liquid which is a mixture of 2-chloroethyl phosphonates, acidity 9.7 meq/100 g. Washing of a 622 g. portion with 5% sodium carbonate solution, followed by stripping at reduced pressure, gives 590 g. acidity 3.7 meq./100 g. Distillation of a portion of the washed material gives bis(2-chloroethyl) 2-chloroethylphosphonate, b.p. 148°-151°/0.5 mm., and 2-chloroethyl 3-[bis(2-chloroethoxy)phosphinyl]propionate, b.p. 189°-191°/0.1 mm, leaving a mixture containing higher molecular weight 2-chloroethyl phosphonates as undistilled residue.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (110 mg, 0.34 mmol) and ammonium acetate (270 mg, 3.4 mmol) in methanol (1.9 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled and sodium cyanoborohydride (43 mg, 0.69 mmol) was added. The reaction was heated at 65° C. for another 4 hours. The mixture was cooled, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (98 mg, 93%). LCMS calculated for C16H17ClFN2O (M+H)+: m/z=307.1. found: 306.9.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(=S)=S>O>[CH2:6]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[C:17]=1[C:22]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:31])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Cc2cc3ccccc3o2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)cc1
Yield: 84.2 %

Procedure:
Tin tetrachloride (6.5 mL, 55.5 mmol) was added dropwise over a 30 minute period to a stirred solution of 2-benzyl-benzofuran (10.0 g, 48.01 mmol), anisoyl chloride (8.51 g, 49.93 mmol) and carbon disulfide (53 mL) at room temperature under a dry nitrogen atmosphere. After 15 h the reaction mixture was added to water and extracted with dichloromethane. Silica gel was added to the dichloromethane phase and the solvent was removed. The adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate as eluent) to provide the title compond as a white solid (13.84 g, 84%): mp 84-85° C.: NMR (CDCl3); δ7.87 (dm, J=9 Hz, 2 H), 7.46 (dm, 1 H), 7.36-7.12 (m, 8 H), 6.97 (dm, J=9 Hz, 2 H), 4.29 (s, 2 H), 3.90 (s, 3 H): MS (EI):
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[C:15]([CH:22]2[CH2:24][CH2:23]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([CH:22]2[CH2:23][CH2:24]2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=C(c2ccccc2)C2CC2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Yield: 102.4 %

Procedure:
[4-(2-Cyclopropyl-2-phenyl-vinyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (94 mg, 0.28 mmol) is dissolved in methanol (1.5 mL) and DCM (1.5 mL). Then 5% palladium on carbon (59 mg, 0.028 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give 97 mg of the crude product which is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([CH:15]=[O:16])[C:11]=3[CH:17]=2)=[N:4][N:3]=1.C1(C)C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[O:16][CH:29]=[N:28][CH:27]=4)[C:11]=3[CH:17]=2)=[N:4][N:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nnc(-c2ccc3occ(C=O)c3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4cnco4)c3c2)o1
Yield: 20.2 %

Procedure:
A suspension of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carbaldehyde (500 mg, 2.19 mmol), p-toluenesulfonylmethyl isocyanide (471 mg, 2.41 mmol) and potassium carbonate (363 mg, 2.63 mmol) in methanol (10 mL) was heated under reflux for 7 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from methanol to give the title compound (118 mg, yield 20%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([C:7]([Cl:20])=[O:8])[CH:10]=[C:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1cc(C(=O)O)cc(C(=O)OC)c1
Product: C=CCOc1cc(C(=O)Cl)cc(C(=O)OC)c1

Procedure:
A solution of 2.17 g (9.18 mmol) of 5-allyloxy-isophthalic acid monomethyl ester in 9.2 ml of thionyl chloride is heated to reflux for 1 h. Excess thionyl chloride is removed under reduced pressure to yield 3-allyloxy-5-chlorocarbonyl-benzoic acid methyl ester in the form of a color-less oil, which is used without further purification. To a solution of 2.36 g (9.18 mmol) of 3-allyloxy-5-chlorocarbonyl-benzoic acid methyl ester in 9 ml of DCM 27.6 ml of a 1 M solution of dimethylamine in THF (3 eq.) are added at 0° C. The mixture is stirred at rt for 2 h. 100 ml of a half-saturated aq ammonium chloride solution are added. The mixture is extracted with TBME (2×75 ml), and the combined organic layers are washed with 50 ml of water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (EtOAc) to give the product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.Cl.C(N)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[O:8][C:9]([CH3:17])([CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(N)=O
Agent: CCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCCN
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[2-(2-aminocarbonylethyl)phenoxy]-2-methylpropionate (2.7 g, 8.68 mmol) was dissolved in tetrahydrofuran (5 mL). Subsequently, under nitrogen atmosphere, borane-tetrahydrofuran complex in tetrahydrofuran solution [1.0M BH3-THF in THF (26.1 mL, 26.1 mmol)] was added thereto, the mixture was stirred for three hours at 50° C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0° C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (1.44 g, 4.91 mmol, 57%).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]=[C:20]=[S:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]3[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:20]3=[S:21])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: S=C=Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (6.7 g), indan-5-yl-isothiocyanate (7.7 g), triethyl amine (12 g) and chloroform (300 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL) then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethyl acetate to give the title compound (7.9 g) as a tan solid, m.p. 158°-160° C. Anal. Calcd. for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.30; H, 5.81; N, 11.31. Mass spectrum (EI, M.+) m/z 246.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=C.[H-].[Na+].Cl.ClCC[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>CN(C=O)C.O>[N:20]1([CH2:3][CH2:1][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:5]2=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCN1CCCCC1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (35 g, 0.2 moles) in DMF (250 ml) was added dropwise to a suspension of 80% sodium hydride (6 g, 0.2 moles) in DMF (50 ml). The reaction mixture was first heated at 45° C. for 30 minutes, allowed to cool at room temperature, and an additional amount of 80% sodium hydride (7.2 g, 0.24 moles) was added. Then 1-(2-chloroethyl)piperidine hydrochloride (44.16 g, 0.24 moles) was added portionwise and the reaction mixture was heated at 80° C.-90° C. for 3 hours. The mixture was then cooled at room temperature, adjusted to pH 3 with 37% aqueous HCl, and heated to 80° C. for additional 2 hours. The reaction mixture was poured into water and washed with ethyl acetate. The aqueous phase was adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted into ethyl acetate. The organic layer was taken to dryness to give an ivory solid which after crystallization from isopropyl ether afforded 22.9 g of the title compound. M.p. 123° C.-125° C.
Reaction SMILES: CN(OC)[C:3](=[O:6])[CH2:4][F:5].[Li][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[F:5][CH2:4][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: [Li]c1cccnc1
Reactant: CON(C)C(=O)CF
Product: O=C(CF)c1cccnc1

Procedure:
N-Methyl-N-methoxyfluoroacetamide (D6) (12.64 g, 0.104 mol) was treated with 3-lithiopyridine as in the method of Description 7 to afford 3-(α-fluoroacetyl)pyridine (9.63 g). This crude material was taken-up in dry methanol (100 ml) and treated with methoxylamine hydrochloride (6.63 g, 0.076 mol) at reflux for 1 h. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous potassium carbonate (100 ml) and chloroform (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in ether and insoluble material was removed by filtration. The solvent was removed in vacuo and the residue was distilled to afford the title compound (D9) as an oil (10.22 g, 58%) b.p. 110° C. at 0.5 mmHg (Kugelrohr), which consisted of a 4:1 mixture of Z and E isomers.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95