Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].CS(C)=O.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[C:34]([CH:35]=O)=[C:33]([OH:41])[CH:32]=1>>[CH3:40][O:39][C:37]1[C:34]([CH2:35][CH2:1][CH3:2])=[C:33]([OH:41])[CH:32]=[C:31]([O:30][CH3:29])[CH:38]=1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CCCc1c(O)cc(OC)cc1OC
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Triphenylphosphine ethylbromide (4.1 g) was added to a 2N sodium hydride/dimethyl sulfoxide solution (11 ml), prior to agitation at 50° C. for 30 minutes. To the mixture was added 4,6-dimethoxy-2-hydroxybenzaldehyde (1 g), for agitation at 50° C. overnight. After the termination of the reaction, the resulting solution was partitioned with ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-2-propylphenol (0.5 g; yield of 46%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[H-].[Na+]>O>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1cc([N+](=O)[O-])c(-n2ccnc2)cc1F

Procedure:
12 g (0.068 mol) of 5-amino-2,4-difluoronitrobenzene were slowly added at 0° C. to a solution of 4.7 g of imidazole (0.069 mol) and 2.1 g of sodium hydride (80% in oil; 0.07 mol) and then stirred at this temperature for several hours. The mixture was then diluted with water and extracted several times with methylene chloride. The residue after drying and evaporation was recrystallized from isopropanol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:11]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1nn(C)c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To an acetonitrile (5 ml) solution of methyl 6-(trifluoromethyl)-1H-indazole-3-carboxylate (300 mg, 1.2 mmol) were added potassium carbonate (1.0 g, 7.4 mmol) and iodomethane (350 mg, 2.5 mmol) at room temperature respectively. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and washed with acetonitrile. The filtrate was concentrated in vacuo. After being filtered off, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel chromatography column and eluted with a hexane/ethyl acetate=4/1 to furnish 239 mg (75% yield, major product) of the title as a white solid;
Reaction SMILES: [H-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:7]=1[N+:13]([O-:15])=[O:14].C[CH2:17][O:18]C(C)=O>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:18][CH3:17])[C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
252 mg of sodium hydride as a 60% suspension in oil (6.29 mmol) are placed in a 100 mL three-necked flask containing 10 mL of THF and 0.255 mL of MeOH. The mixture is stirred at room temperature for 1 hour, and a solution of 2,6-difluoronitrobenzene 47 (1.0 g, 6.29 mmol) in 10 mL of THF is added. The reaction medium is left at room temperature for 16 hours. 10 mL of EtOAc are added and the resulting mixture is washed twice with 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and finally evaporated to dryness. 0.93 g of product 52 is obtained (cream-coloured solid).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[NH2:7].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>CO>[CH3:12][O:11][C:9]1[CH:10]=[C:4]([O:3][CH3:2])[CH:5]=[C:6]2[C:8]=1[C:13](=[O:17])[C:14](=[O:15])[NH:7]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethoxyaniline hydrochloride (54.7 g), oxalyl chloride (54 ml) and methanol (500 ml) was stirred and heated to reflux for 1.5 hours. The mixture was cooled to ambient temperature. The precipitate was isolated, washed in turn with methanol and diethyl ether and dried under vacuum to give 4,6-dimethoxy-2,3-dioxoindoline (55 g); NMR Spectrum: (DMSOd6) 3.85 (s, 3H), 3.9 (s, 3H), 6.0 (s, 1H), 6.2 (s, 1H), 10.9 (s, 1H); Mass Spectrum: M+Na+ 230.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]([NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:25](=[O:26])[CH2:24][CH2:23][NH:22][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: COC(=O)CCCCCN
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
The compound 35 was prepared using General Procedure B with 6-aminohexanoic acid methyl ester hydrochloride salt (3.0 g, 16.5 mmol), N-Cbz-β-alanine (3.68 g, 16.5 mmol), 1-hydrobenzotriazole (HOBt) (2.68 g, 19.8 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC) (3.80 g, 19.8 mmol) and Et3N (5.52 mL, 39.6 mmol) in CH2Cl2, (100 mL). Recrystallization of the crude product from a mixture of MeOH and H2O (10:1 ratio) afforded 5.28 g (91%) of the desired product (35) as a white solid. 1H NMR (CDCl3): 7.32 (m, 5H, ArH), 5.82 (s, 1H, NH), 5.54 (s, 1H, NH), 5.07 (s, 2H, OCH2Ar), 3.64 (s, 3H, OCH3), 3.45 (dt, J=6.1, 12.0 Hz, 2H, CH2NHCO), 3.21 (dt, J=6.4, 12.8 Hz, 2H, CH2NHCO), 2.38 (dt, J=6.1, 6.8 Hz, 2H, CH2CO), 2.29 (t, J=7.2 Hz, 2H, CH2CO), 1.61 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.33 (m, 2H, CH2).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(O[C:9](=O)[CH3:10])(=O)C.[NH2:12][CH:13](O)[CH2:14]CC>C(#N)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:1]([O:4][CH2:14][C@H:13]([NH2:12])[CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(N)O
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: CC[C@@H](N)CO[N+](=O)[O-]
Reaction time: 1 h
Yield: 93 %

Procedure:
(2R)-Aminobutan-1-ol (1.01 g, 11.3 mmol) was dissolved in anhydrous acetonitrile (50 mL) and the solution was cooled using an ice bath. To the solution, fuming nitric acid (0.5 mL) was added. A mixture of acetic anhydride (8.3 mL, 90 mmol) and fuming nitric acid (2.3 mL, 57 mmol) were cooled in an ice bath and then added slowly to the aminobutan-1-ol reaction mixture and stirred for 1 hour. Solvent was removed under reduced pressure and the residue obtained was dried overnight under high vacuum to yield the title compound (2.07 g, 10.5 mmol, 93% yield) as a light green solid. 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H), 4.75 (dd, J=11.9 and 2.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.46 (s, 1H), 1.61 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3, 75.45 MHz) δ 72.1, 49.7, 22.5, 9.5. LRMS (APIMS) m/z 135 (M−HNO3+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([CH3:28])[O:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:23][C:24]([NH:26][CH3:27])=[O:25])[CH2:15]1.O>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][N:26]([CH3:27])[C:24](=[O:25])[O:23][C:20]2[C:21]3[O:22][C:14]([CH3:13])([CH3:28])[CH2:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: c1ccncc1
Solvent: O
Product: CN(Sc1ccc(C(C)(C)C)cc1)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 8 h

Procedure:
One-half (by volume) of the resultant solution of 4-(tert-butyl)benzenesulfenyl chloride was added to a solution of 10.9 g of carbofuran in 30 ml of pyridine. The mixture was allowed to stand overnight, then poured into water. The water-insoluble material was washed several times with water, then dissolved in ether. The ether solution was washed with water and dried. Removal of the ether under reduced pressure gave a solid which on recrystallization from hexane-ether gave 7.5 g of solid, m.p. 120°-3°. Four recrystallizations from hexane gave 2,3-dihydro-2,2-dimethyl-7-benzofuranyl [4-(tert-butyl)phenylthio] (methyl)carbamate, m.p. 122°-123°. The n.m.r. spectrum was consistent with the assigned structure.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].Br[CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH3:19][CH:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(C)Br
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium ethoxide was prepared from sodium metal (7.61 g) and absolute ethanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise to the ethanol containing sodium ethoxide. After heating to 80° C., 2-bromopentane (50 g) was added and the mixture was reflued for 24 h. Diethyl (2-pentyl)malonate (62.7 g) was obtained after the usual work-up. Diethyl (2-pentyl)malonate was added to a 50% potassium hydroxide solution and the mixture was heated for 3 h while water/ethanol being distilled off. After cooling, the solution was acidified with concentrated hydrochloric acid. Then, the solution was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting product was heated to 180° C. until bubbling ceased. After distillation, colorless 3R,S-methy-caproic acid was obtained. Yield: 27.7 g (35%), b.p. 200° C./760 mmHg.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[N:16]=[CH:15][CH:14]=[N:13][C:12]=1[S:11]2.Cl>CN(C=O)C>[OH:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[N:16]=[CH:15][CH:14]=[N:13][C:12]=1[S:11]2
Reactant: COc1ccc2c(c1)Sc1nccnc1N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2c(c1)Sc1nccnc1N2
Yield: 23 %

Procedure:
Sodium hydride (60 mg, 2.5 mmoles) was added to ethanethiol (124 mg, 2 mmoles) in dry DMF (2 ml) under argon. 7-Methoxy-1,4-diaza-10H-phenothiazine (462 mg, 2 mmoles) was then added and the reaction mixture was refluxed for 3 hours. The mixture was poured into 0.5N HCl (50 ml). The solid was collected, washed with methanol and air-dried to yield starting material. Extraction of the filtrate with ethyl acetate gave 100 mg of a mixture that was chromatographed on silica gel, eluting with 40% ethyl acetate in hexane to yield 25 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH:28][CH2:29][C:30]6[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=6)=[N:25][N:24]=5)[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH:28][CH2:29][C:30]6[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=6)=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(-c5ccc(Cl)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(-c6ccc(Cl)cc6)n5)c4c3)s2)cc1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-(4-chlorophenyl)pyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (225 mg, 0.332 mmol) in THF (5 mL) followed by KOH (1.5 mL, 1.50 mmol, 1 M). The mixture was heated in microwave at 80° C. for 90 min, then cooled to RT. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 524 (M+1).
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8])C.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH2:19])=[NH:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[N:19]=[C:4]([OH:11])[CH:5]=[C:6]([CH:7]([CH3:8])[CH3:9])[N:18]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: N=C(N)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Product: CC(C)c1cc(O)nc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
The title compound was prepared from 4-methyl-3-oxo-pentanoic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.20-1.26 (m, 6H), 2.80-2.90 (m, 1H), 6.34 (s, 1H), 7.82(s, 1H), 8.18 (s, 2H), 12.50 (br s,1H); MS: m/z (ESI) 283 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3[N+](=O)[O-])c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccccc3[N+](=O)[O-])c2)=C(C)C1=O
Yield: 97.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2-nitroaniline (0.070 g, 0.142 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.063 g, 0.139 mmol, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[OH-].[NH4+:16]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]([NH2:10])=[O:12])[C:7](=[CH:13][CH:14]=1)[C:8]([NH2:16])=[O:9])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1C(N)=O

Procedure:
Commercial 4-nitrophthalimide (500 g; 2.60 moles; mp 196°-200° C) is added quickly to a stirred solution of 15.6 N ammonium hydroxide (3500 ml). With continued stirring, external heating (water bath, 45° C) is applied until frothing ceases (1 hour). The resulting precipitate is collected, washed with ice water (2 × 400ml) then recrystallized with acetone (2 × 400 ml) and dried to yield 440 g of I as pale yellow crystals; yield, 81%, mp 200°-202° C; lit (6) mp 200° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:8][CH:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Cl:21][C:18]1[CH:17]=[N:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([CH:7]3[CH2:8][CH:6]3[CH2:5][CH2:4][NH2:1])[CH2:10][CH2:11]2)=[N:20][CH:19]=1
Reactant: [N-]=[N+]=NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{4-[2-(2-azidoethyl)cyclopropyl]piperidin-1-yl}-5-chloropyrimidine from step 2 of this example (28 mg, 0,091 mmol) was dissolved in 0.821 mL THF. PPh3 (47.9 mg, 0.182 mmol) was added, followed by addition of 0.091 mL water. The reaction mixture was stirred at room temperature for 1 hour then 40° C. for 3 hours before cooled back to room temperature. The solvent was evaporated in vacuum. The residue was purified by column chromatography eluting with 10% 2M NH3-MeOH/ethyl acetate to give the titled compound. LRMS calc: 280.8; obs: 281.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[C:2]1([NH:1][C:20]2[C:15]([C:12]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1

Procedure:
An improved process for producing diarylamines is to react an arylbromide and an aniline compound in the presence of a suitable catalyst. For example, aniline can be rapidly reacted with 4-bromobiphenyl to form N-phenyl-biphenylamine using palladium acetate ligated with 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane, which is manufactured as Cytop-216 (Cytec Industries), and sodium t-pentoxide base. This reaction proceeds rapidly, in about 4 to 6 hours, to produce the desired diarylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:33]([CH3:35])[CH3:34]>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][CH:33]([CH3:35])[CH3:34])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc1
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 50 ml twice, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 1 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 462.9 mg.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=1)[CH2:2][CH3:3].Cl>O.CO>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCn1cccc1Cc1cccc(NC(N)=O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCN1CCCC1Cc1cccc(NC(N)=O)c1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
1-Propyl-2-(3'-ureidobenzyl)pyrrole 2 g (7.7 mmol), prepared, for example, as described in Preparation 5D, was suspended in 80 ml of water and 20 ml of a 1.044M solution of hydrochloric acid (20 mmol) in methanol. This suspension was hydrogenated at 45 p.s.i. in the presence of 1.45 g of 5% rodium on activated alumina as catalyst, for 1 hour. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The aqueous residue was treated with ammonium hydroxide until an alkaline pH was obtained, and the product extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (2×50 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol-water, thus obtaining 1.1 g (54%) of 1-propyl-2-(3'-ureidobenzyl)pyrrolidine, the title compound. M.P. 101°-104° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH3:9]S(C)=O.[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][O:27]2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: CS(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CN2CCOC(C3(c4ccccc4)CO3)C2)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a mixture of trimethylsulfoxonium iodide (783 mg, 1 equiv.) and sodium hydride (142 mg, 1 equiv.) in dimethylformamide (17 mL) at 0° C. under nitrogen atmosphere was added dimethylsulfoxide (251 μL, 1 equiv.) and the resulting suspension was stirred for 30 minutes. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (1 g, 1 equiv.) in dimethylformamide (10 mL) was then added dropwise. Stirring was continued for 30 minutes and the reaction was stopped by addition of water (50 mL). The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (20/80) to give 825 mg of the title compound as a colourless oil (78%), mixture of two diastereoisomers. LCMS (6 minute method) [M+H]+=296 @ Rt 1.88 min. single peak.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Temperature: 85 °C
Yield: 63 %

Procedure:
1,2-Dibromoethane (1.6 ml, 18.6 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (0.5 g, 1.86 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (1.2 g, 8.7 mmol) in DMF (60 ml) and the mixture was heated at 85° C. for 2 hours, and was then allowed to cool. The insolubles were removed by filtration, and the volatiles were removed from the filtrate by evaporation to give a residue which was purified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (440 mg, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:18]=[O:19])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccccc2C=O)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-formylphenyl-boronic acid gives “A66”; method 1: HPLC/MS: 1.23 min, [M+H]=319;