Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C)N=NN=2)C=[O:11])=CC=1.[C:25]1([P:31](=CC=O)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([P:31](=[O:11])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a mixture of 3,3-bis (4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (71.6 g, 0.22 mole) and triphenylphosphoranylidene acetaldehyde (66.8 g, 0.22 mole) was added 1.1 liters of dry benzene and the suspension was heated to reflux temperature over a period of 30 minutes. The reaction was allowed to proceed at reflux temperature for 2 hrs. Analytical TLC eluted five times with 30% (v/v) ethyl acetate in hexanes showed only one major spot at Rf =0.37 for the desired product. The crude hot reaction mixture was diluted with an equal volume of hexane and the warm mixture was quickly filtered through a bed of activated charcoal. The filtrate was allowed to stand at room temperature from which 58.12 g (75.2%) of the desired product was collected. A second crystallization from the filtrate yielded mostly triphenylphosphine oxide. Concentration of the filtrate yielded an additional amount of the desired product to give a total of 71 g (91.1%) of the title compound. The combined material was recrystallized from ethyl acetate-hexane to give pure title compound; m.p.=164°-165° C. A 1H NMR of the recrystallized material showed no detectable double homologated product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15][CH2:16][N:19]([CH3:20])[CH3:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reactant: CNC
Solvent: CCO
Product: CN(C)CCC1=NC=C(OCc2ccccc2)C(=O)C1
Temperature: 100 °C

Procedure:
A mixture of 5-benzyloxy-2-vinyl-4-pyridone (3.12 g), 50% aqueous solution of dimethylamine (15 ml) and ethanol (35 ml) was heated at 100° C. in a sealed tube for 8 hours. The resulting mixture was cooled and concentrated under reduced pressure to dryness. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give 5-benzyloxy-2-[2-(N,N-dimethylamino)ethyl]-4-pyridone (3.45 g) as a powder.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[C:37](O)(=[O:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:39])[CH3:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) in DMF (2.2 ml) was added N,N-diisopropylethylamine (252 mg, 334 μl, 1.95 mmol), acetic acid (21.6 mg, 20.6 μl, 360 μmol) and TBTU (154 mg, 480 μmol). The mixture was allowed to stir at room temperature for 4 h, poured into ice/water (5 ml) and 1N NaOH (5 ml) and extracted with dichloromethane/MeOH (9:1, 20 ml). The organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (0.13 g) was triturated with dichloromethane (1 ml) and heptane (5 ml) for 30 min, the precipitate was collected by filtration, washed with heptane and dried to yield the title compound as a white solid (95 mg, 85%), MS (ISP) m/z=372.9 [(M+H)+], mp 195° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([OH:20])=O)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[N:6][C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.Cl>O.CN(C)C=O>[Cl:27][C:23]1[CH:22]=[C:21]([C:5]2[N:6]=[C:7]([N:9]3[C:13]4[CH:14]=[C:15]([C:18]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:20])[CH:16]=[CH:17][C:12]=4[N:11]=[CH:10]3)[S:8][C:4]=2[C:1]([NH2:2])=[O:3])[CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(C(=O)O)cc32)nc1-c1cccc(Cl)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.05 g (0.15 mmole) of 3-[5-Carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazole-5-carboxylic acid (I.10a), 0.050 mL of N-methyl-piperazine, 0.070 g (0.18 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 4 mL of dimethylformamide was stirred at room temperature for 16 hours. The mixture was poured into 50 mL of water and made acidic by addition of 1 M hydrochloric acid. The aqueous layer was extracted three times with 20 mL of ethyl acetate and then made basic by addition of potassium carbonate solution. The mixture was extracted three times with 20 ml, of ethyl acetate. The combined organic extracts were washed with 20 mL of water, 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (7:93) to give 0.021 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazine-1-carbonyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.11) as a yellow solid. MH+/Z=481
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:13][OH:14].N1C=CC=CC=1.[Cl:21][C:22]([C:32]([F:35])([F:34])[F:33])=[CH:23][C@@H:24]1[C@H:26]([C:27](Cl)=[O:28])[C:25]1([CH3:31])[CH3:30].CCCCCCC>C1(C)C=CC=CC=1>[Cl:21][C:22]([C:32]([F:33])([F:34])[F:35])=[CH:23][C@@H:24]1[C@H:26]([C:27]([O:14][CH2:13][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:2]=2[CH3:1])=[O:28])[C:25]1([CH3:31])[CH3:30]
Reactant: Cc1c(CO)cccc1-n1cccc1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: Cc1c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)cccc1-n1cccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 2.0 grams (0.011 mole) of 2-methyl-3-(pyrrol-1-yl)phenylmethanol (prepared in Example 2), and 0.9 gram (0.011 mole) of pyridine in 30 ml of toluene was warmed to 50° C. Under a dry-nitrogen atmosphere 2.8 grams (0.011 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 2 ml of toluene was added in one portion. The addition caused an exothermic reaction which raised the reaction mixture temperature from 50° C. to 55° C. Upon complete addition the reaction mixture was heated to 60° C. where it was stirred for 2.5 hours. The reaction mixture was cooled and poured into a separatory funnel with 300 ml of heptane. The resultant organic layer was washed with 100 ml of an aqueous solution of 2 N hydrochloric acid then with 200 ml of an aqueous solution of 2 N sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by distillation using a Kugelrohr distilling system to give 3.8 grams of [2-methyl-3-(pyrrol-1-yl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate, bp 135° C./0.04 mm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH2:19].C(=O)(O)[O-]>ClCCl.CN(C)C=O.N1C=CC=CC=1>[CH3:18][NH:19][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: CN
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccnc(Cl)n1
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-pyrimidine-4-carboxylic acid (200 mg, 1.3 mmol) in dichloromethane (10 ml) cooled in an ice/water bath was added oxalyl chloride (0.7 ml) and dimethylformamide (3 drops). The reaction was incomplete after 45 minutes so a further portion of oxalyl chloride was added (0.7 ml) and the reaction allowed to proceed at room temperature for a further hour. The reaction was then concentrated and to the crude acid chloride was added pyridine (0.1 ml) and methylamine hydrochloride (0.16 g, 1.9 mmol). After stirring for 3 hours a further portion of both reagents were added and the reaction left to stir overnight. To the reaction was added dilute bicarbonate solution and the mixture was extracted with dichloromethane. The organic liquors were concentrated to furnish the title compound as a yellow solid (150 mg). 1H NMR (400 MHz, DMSO-d6): 9.01 (1H, d), 8.99-8.88 (1H, m), 8.01 (1H, d), 2.83 (3H, d).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[CH:12][CH:11]=1)#[N:9]>ClCCl>[C:8]([C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH:18][CH3:2])=[CH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cccc(Oc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous trifluoroacetic acid (20 ml) was added to 20 ml of dichloromethane solution containing 1.53 g of 3-(4-cyanophenoxy)aniline, and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in 40 ml of 2-butanone. Then, 3.14 g of methyl iodide and 2.09 g of potassium carbonate were added thereto. The reaction mixture was heated for 3 hours under reflux, insoluble materials were separated by filtration, and the solvent was evaporated under a reduced pressure. To the thus obtained residue were added 30 ml of methanol, 20 ml of water and 1.10 g of potassium carbonate. The reaction mixture was heated for 2 hours under reflux, diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluant; hexane:ethyl acetate=2:1) to obtain 1.52 g of 3-(4-cyanophenoxy)-N-methylaniline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13]Br)=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH3:18])[N:3]=1.[OH2:19]>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH2:13][OH:19])=[CH:11][CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH3:18])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccc(CBr)o2)c1C#N
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CSc1nc(N)nc(-c2ccc(CO)o2)c1C#N
Reaction time: 16 h
Yield: 35 %

Procedure:
To a stirred suspension of 100 mg (0.31 mmol) 2-amino-4-(5-bromomethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 5 ml water and 5 ml acetone was added 104 mg (0.61 mmol) silver nitrate and stirring continued for 16 h at room temperature in the dark. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane then acetone) afforded 28 mg (35%) 2-amino-4-(5-hydroxymethyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile e as an orange crystalline solid. EI-MS m/e (%): 262 (M+, 100), 261 ([M—H]+, 90).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH:14]([CH3:16])[CH3:15]>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:18]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(C)CN=C=S
Agent: Cl
Product: CC(C)CNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isobutyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 262°-264° C.; 1H-NMR (DMSO-d6): δ 0.90 (d, 6H), 2.85 (m, 1H), 3.02 (t, 2H), 7.08 (s, 1H), 7.3 (br. s, 1H), 10.9 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[CH2:21][O:22][CH2:23][O:24][CH3:25])CCC.C(OCC)(=O)C.O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2[N:5]=[N:6][CH:7]=[C:2]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: Fc1ccc(-c2cc(Cl)cnn2)cc1Cl
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
5-Chloro-3-(3-chloro-4-fluoro-phenyl)-pyridazine (535 mg, 2.2 mmol) and bis-(triphenylphosphine) -palladium(II)-dichloride (145 mg, 0.22 mmol) were treated with a solution of tributyl-methoxymethoxymethyl-stannane (Sawyer J. S.; Kucerovy A.; Macdonald T. L.; McGarvey G. J. J. Am. Chem. Soc. (1988), 110, 842-853) (964 mg, 2.64 mmol) in DMF (5.3 ml). The mixture was heated at 100° C. for 4 hours then cooled to room temperature and a saturated KEF solution (5.3 ml) was added. The mixture was stirred for 30 minutes at room temperature and ethyl acetate and water were added. The mixture was filtered and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 7:3) to provide 3-(3-chloro-4-fluoro-phenyl)-5-methoxymethoxymethyl-pyridazine (370 mg, 60%) as a pale yellow solid, MS: m/e=283.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]#[N:13])[CH:7]=[CH:8][N:9]=1
Reactant: Brc1cccc2ccncc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 70.5 h

Procedure:
To a solution of 0.5035 g (2.42 mmol) 24 in 10 mL DMF was added 0.1713 g (1.45 mmol) zinc cyanide and 0.1687 g (0.15 mmol) tetrakis(triphenylphosphine)palladium(0). After 70.5 h under argon at 80° C., the reaction mixture was cooled to room temperature, diluted with 50 mL toluene and washed with 15 mL 2N NH4H. The aqueous layer was extracted with 15 mL toluene. The combined organic layers were washed with 15 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×105 mm silica gel, linear gradient 1-4% MeOH:CH2Cl2) yielded 25. 1H NM (CDCl3, 400 MHz) δ 9.679 (s, 1H, ArH); 8.732 (d, 1H, J=5.67 Hz, ArH); 8.097 (d, 1H, J=8.41 Hz, ArH); 8.031 (d, 1H, J=7.13, ArH); 7.771 (dd, 2H, J=6.81, 10.47 Hz, ArH); MS (Electrospray): m/z 155.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:11]=2[NH2:12])=[N:4][N:3]=[N:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1nnn[nH]1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1nnn[nH]1

Procedure:
3-(1H-Tetrazol-5-yl)-4′-trifluoromethyl-biphenyl-4-ylamine (0.5 g) and 4-choro-3-trifluoromethyl-phenyl isocyanate (0.4 g) in toluene (15 mL) was stirred at room temperature for two days. The reaction mixture was evaporated to an oil, the oil was dissolved in acetone and filtrated through Celite, the filtrate was added water, the product precipitated and was isolated by filtration. Yield 0.6 g Mp. 226-228° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19].Cl>ClCCl.C1(C)C=CC=CC=1>[N:2]([C@@H:3]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:18]=[O:19]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@H](N=C=O)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To 25.00 g (137.62 mmol) of methyl(2S)-2-aminohexanoate hydrochloride in 458 mL of dichloromethane at 0° C. was added 44.52 mL (550.49 mmol) of pyridine. Then, 85.57 mL (165.14 mmol) of a 1.93 M solution of phosgene in toluene was added to the solution and the mixture was stirred at 0° C. for 3 h. The solution was poured into 1N hydrochloric acid at 0° C. and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by vacuum distillation at 80° C. @ 2 torr to give 21.32 g (91%) of methyl(2S)-2-isocyanatohexanoate. Rf=0.46 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6)δ 4.37 (dd, J=7 Hz, J=5 Hz, 1H), 3.73 (s, 3H), 1.78-1.60 (m, 2H), 1.36-1.16 (m, 4H), 0.85 (t, J=7 Hz, 3H); ES-MS m/z 172 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl>CO.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cc3c(-c4ccccc4)n[nH]c3cn2)cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (54.5 mg, 0.152 mmol) in MeOH (8 mL) was added 6 M HCl in water. The reaction mixture was stirred at 60° C. under N2 for 16 h. The reaction mixture was cooled to room temperature. Volatile solvent was removed under reduced pressure. The crude was redissolved in EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. Crystallization from DCM-heptanes afforded 133 as a solid (40 mg, 95.8%). 1H NMR (400 MHz, DMSO) δ 13.71 (broad s, 1H), 9.04 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.09 (d, J=7.3 Hz, 3H), 7.55 (t, J=7.5 Hz, 2H), 7.44 (t, J=7.4 Hz, 1H), 3.90 (s, 3H). LC/MS: m/z 276.1 [M+1]
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[CH:15](OC)(OC)OC.B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[CH3:15][O:11][C:10]1([CH3:12])[CH2:9][CH2:8][CH:7]2[C:2](=[CH2:1])[CH:3]1[CH2:4][CH2:5][C:6]2([CH3:14])[CH3:13]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: COC(OC)OC
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=C1C2CCC(C)(OC)C1CCC2(C)C
Yield: 85.4 %

Procedure:
120 g (0.563 mol) of dihydro-α-ionone, 65 g (0.612 mol) of trimethyl orthoformate and 200 ml of methylene chloride are treated dropwise while stirring during 15 minutes with a solution of 8 g of boron trifluoride etherate in 60 ml of methylene chloride and the mixture is subsequently held under reflux for 105 minutes. The reaction mixture is cooled and poured into 500 ml of a 5% aqueous potassium hydroxide solution. After the addition of 500 ml of methylene chloride and vigorous intermixing the phases are separated, the organic phase is washed with water and the solvent is distilled off. The residue (197.1 g) is fractionated in a vacuum over a 15 cm Widmer column. There are obtained 100.2 g of product of b.p. 44°-47°/0.06-0.07 mbar (yield 87% of theory based on pure dihydro-α-ionone) as a colorless liquid which contains 72.3% of exo isomer and 20.1% of endo isomer of the desired bicyclo-nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(C)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(C)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-methyl-quinoline-3-carboxylic acid ethyl ester (125 mg, 0.5 mmol) was treated with cyclopentylamine following general procedure B to afford 4-Cyclopentylamino-8-methyl-quinoline-3-carboxylic acid ethyl ester (120 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (90 mg) following general procedure E.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8](O)=[O:9])[N:3]=[CH:4][CH:5]=1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[CH3:15][C:12]1[CH:13]=[CH:14][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[C:7]([CH:11]=1)[C:8]([Cl:19])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (15, 3.56 g, 17.52 mmol) in DCM (150 mL) cooled to 0° C. was added oxalyl chloride (1.90 mL, 21.9 mmol) and DMF (68 μL, 0.89 mmol). The solution was slowly warmed to ambient temperature and stirred overnight. The mixture was concentrated in vacuo and the resulting solid was azeotroped with DCM and concentrated in vacuo to provide 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (3) as a yellow solid.