Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]2[C:23](=O)[CH2:24][CH2:25][C:3]=12.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[C:17]1([C:14]2[N:13]=[CH:12][C:11]([C:10]3[CH:9]=[N:8][N:7]4[C:2]([NH2:1])=[C:3]5[CH2:25][CH2:24][CH:23]([NH:33][CH:30]6[CH2:31][CH2:32][O:27][CH2:28][CH2:29]6)[C:4]5=[N:5][C:6]=34)=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(=O)CC2
Reactant: NC1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C(NC1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-amino-3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-5-one (61.5 mg, 0.18 mmol), tetrahydro-2H-pyran-4-amine (100 uL), HOAc (100 uL) in EtOH (2 mL) was stirred at room temperature for 15 min. NaBH3CN (56.7 mg, 0.90 mmol) was added and the reaction was stirred overnight. Purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-N5-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine-5,8-diamine: LCMS tR=2.35 Min (10 min run, UV254nm), Mass calculated for, M+426.0, observed LC/MS m/z 427.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CC(C)=O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][C:20](=[O:21])[CH2:19][Cl:18])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1)=[O:21]
Reactant: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Reactant: O=C(Cl)CCl
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc2c(c1)S(=O)(=O)c1cc(NC(=O)CCl)ccc1-2
Temperature: 100 °C

Procedure:
A slurry of 21.8 g of 3,7-diaminodibenzothiophene S,S-dioxide in 400 ml of acetone was cooled in an ice bath while 30.2 ml of chloroacetyl chloride was carefully added. The bath was removed and the mixture heated at 100° C. with stirring, then cooled and poured into ice water. The precipitate was collected, washed with water and dried giving 34.9 g of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClCCl.[CH3:43][NH:44][CH3:45]>O1CCCC1>[Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=[O:25])[N:44]([CH3:45])[CH3:43])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.065 g, 51%). 1H NMR (400 MHz, DMF-d6) δ 7.58 (app q, J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt, J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2N3O3 requires 506.0885).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.ClC1C=CN=CC=1.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:21]>O1CCOCC1>[N:21]1([C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]([O:27][CH3:28])=[O:26])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC(=O)c1ccccc1N
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-n1cccc1
Yield: 92.7 %

Procedure:
17.14 mol of 2,5-dimethoxytetrahydrofuran and 19.84 g of 4-chloropyridine hydrochloride in 600 ml of 1,4-dioxane are stirred for 10 minutes at 25° C., and then 17.12 mol of methyl anthranilate are added and the suspension is heated at reflux for 3 hours. After removal of the dioxane under reduced pressure, the residue is taken up in 1 liter of water and extracted with diethyl ether. The ethereal phase is washed with water, decanted off, dried over magnesium sulfate, rendered colourless with animal charcoal, and then concentrated under reduced pressure to yield the title product in the form of an oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]1[CH2:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[Li][CH2:22][CH2:23]CC.[CH3:26][CH2:27]CCCC.C(I)C>C1COCC1>[CH2:22]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]1[CH:13]([CH2:26][CH3:27])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:23]
Reactant: C1=C(CCC2=Cc3ccccc3C2)Cc2ccccc21
Reactant: CCCCCC
Reactant: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1C(CCC2=Cc3ccccc3C2CC)=Cc2ccccc21
Temperature: -10 °C
Reaction time: 2 h

Procedure:
1.36 g, 5.26 mmol of 1,2-bis(2-indenyl)ethane, prepared as described in the above reported Synthesis 1(a), were dissolved in 25 mL THF and cooled to −10° C. 5.5 ml of a 1.6 M solution of BuLi in hexane (8.8 mmoles) were added and the resulting orange/brown solution was stirred for 2 hours, at room temperature. To the obtained ;mixture was added, by means of a cannula, a solution of 1.1 ml of EtI (7.1 mmol) in 10 ml THF, at −10° C. After 2 hours, the THF was removed under vacuum, and Et2O was added. The thus obtained ether solution was washed 3 times with a saturated solution of NaHCO3 and 3 times with a saturated aqueous solution of NaCl. After drying over MgSO4, 1.46 g of 1,2-bis(1-ethyl-2-indenyl)ethane was isolated, in the form of a yellow oil. 1H NMR and GC showed that it consisted of the three possible double bond isomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[C:19]([CH3:24])[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:22]=2)[CH:7]=1
Reactant: Cc1cc(N)nc(C(C)C)c1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C(C)C)n1
Temperature: 140 °C
Yield: 29.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (260 mg, 1.18 mmol) in acetonitrile (3.9 mL) was added 6-isopropyl-4-methylpyridin-2-amine (265 mg, 1.76 mmol) and then the mixture heated at 140° C. for 48 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 5 to 30% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate (117 mg, 349 μmol, 30%) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.60 (s, 1H), 9.39 (s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 4.58 (q, J=7.0 Hz, 2H), 3.04 (m, 1H), 2.35 (s, 3H), 1.53 (t, J=7.1 Hz, 3H), 1.35 (d, J=7.0 Hz, 6H), MS (EI/CI) m/z: 335.0 [M+H].
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:6]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])ccc(C(=O)N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180 mg, 0.97 mmol) in DCM (8 mL) was added morpholine (0.17 mL. 1.9 mmol), DIEA (0.25 mL) and HBTU (0.4 g, 1.05 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with water and extracted with DCM (3×). The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography to give (2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone (0.20 g, 83%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].I[CH3:27]>C1COCC1.[Ag]=O>[CH3:27][O:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25]
Reactant: CI
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
(+/−)-Tert-butyl (1R,5S,6R)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) was suspended in iodomethane (100.0 equiv.). Silver oxide (6.0 equiv.) was added to the mixture and the reaction vessel was wrapped in foil (kept dark) and allowed to stir 45° C. for 10 hrs. The reaction was diluted with THF and filtered through a pad of celite. The celite cake was further washed with MeOH. The organics were concentrated and the crude was taken up in DCM, washed with NaHCO3(aq), dried over Na2SO4, filtered and concentrated. The crude was loaded onto silica gel and purified via ISCO to yield (+/−)-tert-butyl ((1R,5S,6R)-6-methoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate in 35% yield. LC/MS (m/z)=364.1 (MH+), Rt=0.89 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:18][CH:19]4[CH2:21][CH2:20]4)[N:16]=[N:17][C:13]=3[C:12]=2[C:24]([F:27])([F:26])[F:25])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].O>O1CCCC1>[CH:19]1([CH2:18][N:15]2[C:14]3[CH:22]=[CH:23][C:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[C:13]=3[N:17]=[N:16]2)[CH2:21][CH2:20]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
5-[4-(Azidomethyl)phenyl]-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (162 mg, 0.435 mmol) and triphenylphosphine (342 mg, 1.30 mmol, 3 equiv) were combined in tetrahydrofuran (10 mL) at ambient temperature. After stirring for 5 minutes, the mixture was placed into a preheated oil bath at 50° C. for 2 hours. The mixture was treated with sodium bicarbonate (1.5 mL, aqueous saturated) and heated for an additional 1 hour at 50° C. The mixture was cooled to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol containing 10% ammonium hydroxide), providing the titled compound as a light green gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:37]([F:40])([F:39])[F:38])[CH2:3][CH2:2]1.[Li+].[OH-].FC(F)(F)C(O)=O>C(O)C.O>[NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:28]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:37]([F:38])([F:39])[F:40])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCC(=O)N(CC=Cc1cc(C(=N)N)ccc1O)c1ccc(OC2CCNCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N=C(N)c1ccc(O)c(C=CCN(C(=O)CCC(=O)O)c2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine (2.0 g) in 100 mL ethanol/H2O (50/50) was added LiOH (0.56 g) at ambient temperature and the resulting solution was stirred at ambient temperature for 4 hours. The reaction was acidified with trifluoroacetic acid, concentrated, separated on HPLC (CH3CN/H2O, gradient) and freeze-dried to afford 4-(piperdin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-(hydroxy)-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[O:27])=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=4)=[O:27])=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[4-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (680 mg), 1 N aqueous sodium hydroxide solution (1.7 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[4-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (620 mg, yield: 94%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 151–152° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[CH3:17][C:18]1[O:19][C:20](=O)[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>C(O)(=O)C>[CH3:17][C:18]1[N:16]([C:3]2[CH:4]=[CH:5][C:6]([C:8]#[C:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][C:2]=2[CH3:1])[C:20](=[O:19])[C:21]2[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:23]=1
Reactant: Cc1cc(C#Cc2ccccc2)ccc1N
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compounds (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 2,5-dihydroxy benzaldehyde (30c, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4c) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([O:14][CH3:15])(=[O:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: COC(C)=O
Reactant: COc1ccc(C=O)cc1
Product: COC(=O)C=Cc1ccc(OC)cc1
Product: COc1ccc(C=CC(=O)O)cc1

Procedure:
The process of claim 1 wherein p-methoxy benzaldehyde is reacted with methyl acetate in step (a); methyl p-methoxycinnamate is formed in step (b) and methyl p-methoxycinnamate and p-methoxycinnamic acid are reacted with a C8 alkanol in step (e) to produce a C8 alkyl p-methoxycinnamate as the product of the process.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH:25]([NH:28][C:29]([NH:21][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22])=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)N=C=O
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(N)=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
2-(4-((3-Chloro-5-(trifluoromethyl)-2-pyridyl)-oxy)phenoxy)propanamide (3.6 g, 0.01 mole) was dissolved in 80 ml. dry toluene. Isopropyl isocyanate (2.55 g, 0.03 mole) was then added and the mixture refluxed for about 16 hours. The toluene was removed by distillation and cold hexane was added. The product precipitated as white crystals, m.p. 135°-137° C.; Yield 3.6 g; 80.7%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CC#N>[CH3:23][O:22][C:18](=[O:21])[CH:19]=[CH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(C2=CCCc3ccccc32)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=CCCc3ccccc32)cc1
Yield: 74 %

Procedure:
Prepared from the Heck coupling of 4-(4-bromophenyl)-1,2-dihydro-naphthalene (2i, compound I, R3=H, X=Br, and n=1) and methyl acrylate in accordance with the general method described in Example IV (J. Chem. Soc. B, 1969, 638-643). Yield 74%; APcI m/z: 332 (M+H+CH3CN+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][CH2:40][CH3:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccc(OC)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1)S(=O)(=O)c1cccc(OC(F)F)c1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Example 1 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and 1-bromopropane to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-propylamino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected to yield the title compound.
Reaction SMILES: [CH2:1]([O:6][CH:7]([C:9]1[CH2:11][CH:10]=1)C)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:12]C(COCCCCCC)=C.C(OCC1CC=1)CCCCC>>[Br:12][C:10]([CH2:9][CH2:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH2:11]
Reactant: CCCCCOC(C)C1=CC1
Reactant: C=C(Br)COCCCCCC
Agent: CCCCCCOCC1=CC1
Product: C=C(Br)CCOCCCCC

Procedure:
This olefin was converted to 1-pentyloxyethyl-cyclopropene in the same manner that 2-bromo-3-hexyloxypropene was converted to 1-hexyloxymethyl-cyclopropene.
Reaction SMILES: [C:1]([O:4][CH:5]=[C:6]([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2].ClS([N:15]=[C:16]=[O:17])(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOCC.CCCCCC>[C:1]([O:4][CH:5]1[NH:15][C:16](=[O:17])[C:6]1([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCC(=COC(C)=O)CC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCC1(CC)C(=O)NC1OC(C)=O
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A solution of the material prepared in Step A (169 gm, 1.19 mol) in CH2Cl2 (300 ml) was cooled in an ice-ethanol bath under N2 and chlorosulfonyl isocyanate (200 gm, 1.41 mol) was added via an addition funnel. The solution was allowed to rise to room temperature and stirred overnight. The reaction mixture was then diluted with Et2O and added to ice-cold NaHCO3 solution containing Na2SO3, keeping the solution below 5° C. during the addition. After the evolution of gas had ceased, the layers were separated and the aqueous layer was extracted with Et2O. The combined ether extracts were washed with H2O, brine and then dried over Na2SO4 before being evaporated to dryness. This gave a dark oil which was diluted with hexane (100 ml) and cooled in the freezer for 2 days. The low melting white solid which formed was filtered off and washed with cold hexane to give 79.2 gm of the title compound.