Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl.[Cl:9][CH2:10][C:11](=[NH:14])OC>CO>[ClH:9].[O:1]=[C:2]1[NH:3][CH2:4][CH2:5][N:6]([C:11](=[NH:14])[CH2:10][Cl:9])[CH2:7]1
Reactant: O=C1CNCCN1
Reactant: COC(=N)CCl
Agent: Cl
Solvent: CO
Product: N=C(CCl)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.1 %

Procedure:
8.64 g of 2-oxopiperazine were added to a solution of 12.4 g of methyl 2-chloroacetimidate hydrochloride in 44.8 ml of anhydrous methanol, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a small amount of insoluble material was filtered off and the solvent was distilled off from the filtrate. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether, giving 18.0 g of 2-(3-oxopiperazin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].[C:69]([O:75][CH2:76]Cl)(=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71]>C(OCC)(=O)C>[C:69]([O:75][CH2:76][N:36]1[CH:37]=[C:33]([CH2:32][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH2:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C@@H:18]([OH:24])[C@H:19]([CH:21]2[CH2:22][CH2:23]2)[OH:20])[N:34]=[CH:35]1)(=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 250 mg (0.4 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 60 mg of 18-crown-6, 250 mg of potassium carbonate and 2 ml of chloromethyl pivalate is stirred at room temperature overnight. Thereafter, the reaction mixture is taken up in ethyl acetate and the ethyl acetate solution is washed with saturated ammonium chloride solution. After drying over sodium sulphate the solution is evaporated under reduced pressure and subsequently, for purification, the crude product obtained (1.3 g) is chromatographed on 120 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 145 mg of [4-[(S)-2-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]ethyl]imidazol-1-yl]methyl pivalate as a colourless solid; MS: 745 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[N:18]=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:8].N1C=CC=CC=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]2[N:18]=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:8])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc2[nH]cnc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccccc2)cc1C(=O)Nc1cnc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
50 mg of 5-Amino-N-(3H-imidazo[4,5-b]pyridin-6-yl)-2-methyl-benzamide (from example k) were dissolved in 0.5 ml dry DMF and 0.5 ml pyridine and treated dropwise at room temperature with 66 mg benzoyl chloride. After 16 hrs the solvents were removed under vacuum and the residue was stirred for 1 hr at room temperature in a mixture of 2 ml methanol and 1 ml concentrated ammonia. Solvents were removed under vacuum and the residue was purified by HPLC/MS in methanol/water/acetic acid. Product containing fractions were pooled and concentrated under vacuum. Precipitated product was collected by filtration and washed with dilute ammonia to yield 11 mg of the title product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33][O:34]C3CCCCO3)[CH:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[O:32][N:31]=[C:30]([CH2:33][OH:34])[CH:29]=4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M40) (314 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].S(O)(O)(=O)=O.[CH3:16][NH:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:18]\[NH:17][CH3:16])/[CH3:9]
Reactant: CNN
Reactant: CC(=O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN/N=C(/C)c1ccccc1Cl
Yield: 184.3 %

Procedure:
A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen and charged with 1-(2-chlorophenyl)ethan-1-one (3.80 g, 24.6 mmol, 1.20 equiv), methylhydrazine sulfate (3.00 g, 20.8 mmol, 1.00 equiv) and ethanol (30 mL). The resulting solution was heated to reflux overnight. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to provide 7.0 g (crude) of (Z)-1-[1-(2-chlorophenyl)ethylidene]-2-methylhydrazine as yellow oil. LCMS (ESI, m/z): 183 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>CN(C)C(=O)C>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:2][NH:1][C:27](=[O:29])[CH3:28])[CH2:4][N:5]=1)=[CH:16]2
Reactant: CN(c1cccc2cc(C3=NCC(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)NCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of N-{2-[5-(aminomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.27 g) in N,N-dimethylacetamide (6 mL) was added acetic anhydride (0.10 mL) at 0° C., and the, mixture was stirred for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was subjected to silica gel column chromatography to give the title compound. (0.20 g, yield 68%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (95:5, volume ratio). melting point 212-213° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][CH:6]=1.C1C(=O)N([I:19])C(=O)C1>CC#N>[I:19][C:6]1[NH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1nc(C)c[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)c1nc(C)c(I)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 4-methyl-1H-imidazole-2-carboxylate (compound 239.1, 100 mg, 0.65 mmol) in CH3CN (10 mL). NIS (218 mg, 0.97 mmol) was added to the reaction. The reaction mixture was stirred for overnight at room temperature, then concentrated under reduced pressure. The residue was dissolved with 30 mL of EtOAc, then was washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (44%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Yield: 81 %

Procedure:
A mixture of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (2.0 g, 7.9 mmole) and a catalytic amount of p-toluenesulfonic acid in 50 ml toluene was heated at reflux for 1.5 hr. The mixture was cooled and washed with saturated sodium bicarbonate solution. The toluene was removed in vacuo and the residue recrystallized from hexane to give the product (81%, mp: 84°-85° C.). Calc'd for C14H15FO2 : C, 71.78%; H, 6.46%. Found: C, 71.33%; H, 6.33%.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:10][C:9]=1[N+:21]([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:10][C:9]=1[NH2:21]
Reactant: COc1c([N+](=O)[O-])cc(C2(C)CC2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)cc(C2(C)CC2)cc1N
Temperature: 25 °C
Yield: 51.1 %

Procedure:
Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution of 2-methoxy-5-(1-methyl-cyclopropyl)-1,3-dinitro-benzene (2.21 g, 8.76 mmol) in ethyl acetate (30 mL). The mixture was heated to reflux for 0.25 h upon which the solution became red in color. The solution was cooled to rt and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, eluted through a plug of silica gel (1% ammonium hydroxide in methylene chloride), and the filtrate was concentrated. The residue was redissolved in Et2O and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to pH=12 with 2.0M NaOH and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide 2-methoxy-5-(1-methyl-cyclopropyl)-benzene-1,3-diamine (860 mg, 52%) as a red oil. ESI MS (m/z 193, M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][F:16])=[CH:6][N:7]=1
Reactant: OCc1ccc(Br)nc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (6-bromopyridin-3-yl)methanol (1.00 g, 5.32 mmol) in dichloromethane (25 mL) at 0° C. was added DAST (0.70 mL, 5.32 mmol) and the resulting solution was stirred at 0° C. for one hour. The mixture was washed with a saturated sodium bicarbonate solution and concentrated. Flash column separation using a 0-10% ethyl acetate/hexane gradient gave FF1 (0.37 g, 37%). LRMS (ES) (M+H)+: observed=190.0/192.0, calculated=190.0/192.0.
Reaction SMILES: N1[C:5]([C:6]2[N:16]=[CH:15][C:9]3[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=3[CH:7]=2)=[N:4][N:3]=N1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:5]([C:6]2[N:16]=[CH:15][C:9]3[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=3[CH:7]=2)=[N:4][N:3]=1
Reactant: O=c1[nH]cnc2cnc(-c3nnn[nH]3)cc12
Reactant: CC(=O)OC(C)=O
Product: Cc1nnc(-c2cc3c(=O)[nH]cnc3cn2)o1

Procedure:
6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one (1.4 g) in acetic anhydride (10 ml) was heated at reflux under N2 for 2.5 hours. The cooled mixture was absorbed onto silica and purified by chromatography to give the title compound 90.14 g) as a beige solid; δH [2H6]DMSO 13.0(1H,bs), 9.30 (1H,s), 8.66 (1H,s), 8.47 (1H,s) 2.75 (3H,s); m/z (M+1+)230.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([O:13][C:14]4[CH:15]=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)nc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (6.52 mg, 0.272 mmol), 5-(hydroxymethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile (80 mg, 0.272 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50.5 mg, 0.272 mmol).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][NH2:14]>O.Cl.C(OCC)C>[N:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])=[N+:14]=[N-:1]
Reactant: O=N[O-]
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
Sodium nitrite (510 mg) dissolved in 2 ml of water was dropped, under cooling with ice, into a solution of 1.0 g of 2-fluorophenylhydrazine hydrochloride in 5 ml of concentrated hydrochloric acid and 6 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 2 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 400 mg of the title compound as a brown oily crude product.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Cl:6][C:7]1[N:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10].Cl>O.CO>[Cl:6][C:7]1[C:8]([C:9]([NH:2][OH:3])=[O:10])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NO)c1cccnc1Cl
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of hydroxylamine hydrochloride (6.75 g) in water (25 ml) was added sodium hydroxide solution (7.65 g sodium hydroxide in 50 ml water) with stirring under ice cooling. To this stirring solution was added methyl 2-chloronicotinate (15.5 g) in methanol. After being stirred at room temperature for 2.5 hours, pH was adjusted to 3.5 with 6N-hydrochloric acid under ice cooling. After 1 hour, the title compound (11.0 g) was obtained by filtering the precipitated crystals and washing with water and, then, a methanol-ether mixture (1:1).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH2:12][CH3:13])[C:9](=[S:14])[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[O:6]1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH2:12][CH3:13])[C:9](=[S:14])[C:8]2[CH:15]=[CH:16][CH:17]=[N:18][C:7]=2[O:6]1
Reactant: CCN1CC(CCCl)Oc2ncccc2C1=S
Reactant: CNC
Agent: Cl
Product: CCN1CC(CCN(C)C)Oc2ncccc2C1=S
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2-(2-Chloroethyl)-4-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-thione hydrochloride, 5.00 g (0.016 mole) was added to 20 ml of anhydrous dimethylamine. The reaction flask was sealed tightly and stirred at room temperature for 6 days. The flask was opened after cooling to 0° C. and dimethylamine allowed to evaporate at room temperature. The residue was taken up in chloroform (100 ml) and washed with dilute aqueous sodium hydroxide (1×30 ml). The chloroform layer was dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residual oil was dissolved in hot cyclohexane. Upon cooling, 1.76 g (39.4%) of light yellow crystals were collected, m.p. 73° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:13]([N:21]=[C:22]=S)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:22]1[NH:21][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: S=C=NCCc1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Product: Cn1c(NCCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Yield: 66.4 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and phenethyl isothiocyanate (2.15 g, 13.2 mmol) were coupled using the procedure of intermediate example one part B to give the title compound as a yellow solid (2.36 g, 66%). 1H NMR (300 MHz, d6-DMSO) δ 8.01 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.21-7.35 (m, 7H), 3.58-3.65 (m, 2H), 3.56 (s, 3H), 2.93-2.98 (m, 2H) ppm.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7].[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>CO>[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:7][C:16]([O:17][C:9]([CH3:14])([CH3:10])[CH3:8])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 188.7 %

Procedure:
To a mixed solvent of methanol (50 ml) and water (100 ml) were added L-phenylalanine methyl ester hydrochloride (21.6 g), sodium carbonate (11.64 g), and a solution of di-tert-butoxydicarbonate (21.8 g) in methanol (100 ml). The resulting mixture was heated to 40° C., followed by stirring for 6 hours. The reaction mixture was concentrated to remove the methanol. The concentrate was extracted by adding ethyl acetate and water. The resulting ethyl acetate layer was washed with 0.1 N hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution and a saturated solution of sodium chloride. The ethyl acetate layer after washed was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off. The solvent was distilled off under reduced pressure to give the target N-tert-butoxycarbonyl-L-phenylalanine methyl ester (26.4 g) in a yield of 95%.
Reaction SMILES: P(Br)(Br)(Br)(Br)[Br:2].O[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1>O>[Br:2][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: BrP(Br)(Br)(Br)Br
Solvent: O
Product: O=C(O)c1ccc(Br)nc1

Procedure:
Phosphorus pentabromide (18 g.) was added carefully to 6-hydroxynicotinic acid (4.17 g) and the resulting mixture was heated with stirring for about 1/4 hour at 70°-80° and then 1 hour at 120°. During the heating, the resulting dark red liquid solidified to a yellow mass. After cooling, the mass was added to iced water, and the resulting white precipitate of 6-bromonicotinic acid was filtered off, washed with water, and recrystallized from aqueous ethanol (yield 4g, m.p. 190°-195°). The compound was used directly in the next stage.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[OH:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH3:27]>C(#N)C>[CH2:26]([O:19][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:27]
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1CC
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 2′-ethyl-2-hydroxybiphenyl-4-carboxylate (3.13 g, 12.2 mmol) in anhydrous ACN (45 mL) was added anhydrous potassium carbonate (5.05 g, 36.6 mmol) followed by ethyl bromide (4.5 mL, 61 mmol). The reaction mixture was heated at 50° C. for 15 hours, and then cooled to RT and filtered. The filtrate was concentrated under vacuum. The oil was taken up with MTBE, treated with activated charcoal, filtered through a Celite pad and concentrated. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a colorless oil (2.73 g, 79%). HPLC (Method A) Rt 5.4 min (Purity: 99.7%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34]CC3C=CC=CC=3)=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:42])[N:7]=1)(=[O:3])[CH3:2]>C(Cl)Cl.CO.[Pd]>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12](=[O:34])[NH:13][N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:42])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OCc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (2.87 g, 5.00 mmol) in DCM (10 ml) and MeOH (50 ml) was evacuated and backfilled 3× with argon, charged with Pd/C (0.532 g, 0.500 mmol), evacuated and backfilled 3× with H2, then stirred at RT under a balloon of H2 for 1 hr. Filtered through celite, eluted with EtOAc and concentrated filtrate in vacuo to obtain (6-chloro-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate. MS: [M+H]+ m/z 484.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:29])[CH:6]=[C:5]([O:30][CH3:31])[C:4]=1[CH3:32].[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:9][C:8]1[C:3]([Cl:2])=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[CH:6][C:7]=1[CH3:29])[CH3:34]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1Cl

Procedure:
By the procedure of Example 1, 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenylphosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester of melting point 106°-107° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].C(Cl)Cl>C1COCC1>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[CH:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=C(c1ccco1)c1ccco1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC=C(c1ccco1)c1ccco1
Reaction time: 2 h

Procedure:
To a solution of 3,3-bis-(2-furanyl)-acrylic acid ethyl ester (1.31 g, 5.66mmol) in THF (15 ml) was added a solution of DIBAL-H (1 M in toluene, 25.5 ml, 25.5 mmol) at −10° C. The reaction mixture was stirred for a further 2 h. A solution of ammonium chloride (2 ml) was added followed by methylene chloride (250 ml) and decalite. The mixture was filtered and the filter was washed with additional methylene chloride (500 ml) and ethanol (100 ml). The combined organic phases were evaporated to give crude 3,3-bis-(2-furanyl)-prop-2-en-1-ol in 953 mg (88%) yield.