Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([N:29]([CH3:59])[C:30]([C:32]1[C:33]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[N:34][N:35]2[C:40]([F:41])=[CH:39][C:38]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:45](O)=[O:46])=[CH:37][C:36]=12)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:41][C:40]1[N:35]2[N:34]=[C:33]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[C:32]([C:30]([N:29]([CH3:59])[C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:31])=[C:36]2[CH:37]=[C:38]([C:42]2[CH:43]=[C:44]([C:45](=[O:46])[NH:12][C:9]3([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[CH2:11][CH2:10]3)[CH:48]=[CH:49][C:50]=2[CH3:51])[CH:39]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.011 g, 0.054 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.054 mmol) and DMF (0.36 mL) was added HATU (0.041 g, 0.11 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.428 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 638 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=3)[NH2:16])=[CH:10][N:4]2[N:3]=1.C(#N)C.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[CH:17]=3)=[CH:10][N:4]2[N:3]=1
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
A 40 mL vial is charged with 5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-aniline (0.85 g, 3.28 mmol), acetonitrile (14 mL) and pyridine (0.450 mL). The mixture is added trimethylacetyl chloride (0.628 mL, 0.0051 mol) and stirred for 20 min at 80° C. The mixture is concentrated, taken up in EtOAc (35 mL) and washed once with HCl (20 mL, 1M) and then NaOH (20 mL, 1M). Organic layer is dried, concentrated and purified on silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (1.05 g, 94% yield). LCMS m/z=343.5 [M+H]+, tR=2.39 min. (compound same as Example 118)
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dichloroethane (20 ml). Benzoyl chloride (0.64 ml) and triethylamine (2.8 ml) were added to the solution under ice-cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol), and recrystallized from ethyl acetate to give 1.50 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)benzamide.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1.C([BH3-])#N.[Na+]>O.C(O)C.C(O)(=O)C>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][CH2:3][CH2:4][CH2:5][N:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COC(CCN1CCCC1)OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(NCCCN3CCCC3)cc2c1Nc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Dissolved 0.64 g (3.69 mmol) 3-(pyrrolidin-1-yl)propionaldehyde dimethyl acetal in 10 ml water and acidified to pH 1 with concentrated HCl. Heated to 40° C. for 90 minutes, removed heat and neutralized with sodium bicarbonate. Dissolved 500 mg (1.47 mmol) 6-amino-4-(3-bromo-phenylamino)-quinoline-3-carbonitrile in 100 ml ethanol and added acetic acid until pH was 3 to 4. Added the deprotected aldehyde to the amine solution and stirred at 25° C. for 0.5 hour. Gradually added 94 mg (1.47 mmol) sodium cyanoborohydride and stirred overnight. Stripped solvent, partitioned between chloroform and water. Washed organic layer with brine and dried with sodium sulfate. Stripped solvent and filtered through a pad of silica gel, first with 10% methanol/chloroform, then 20% methanol/chloroform/1% ammonium hydroxide. Stripped solvent and dried in vacuo, giving 143 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=450, 452.1.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[N:9][C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH3:8])[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.Cl.C(=O)([O-])O.[Na+]>O>[OH:3][CH2:4][CH2:5][C:6]1[C:2](=[O:1])[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[NH:9][C:7]=1[CH3:8]
Reactant: CC(=Nc1cc[nH]n1)C1CCOC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c2ccnn2c(=O)c1CCO
Temperature: 100 °C
Yield: 90.8 %

Procedure:
In 7.5 ml of water were suspended 1.17 g (6.04 mmol) of 3-{[1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino}-pyrazole, and 0.73 g (7.23 mmol) of triethylamine were added to the suspension. The resultant mixture was stirred for 2 hours in an oil bath heated to 100° C. Thereafter, the reaction mixture was cooled with ice water, and concentrated hydrochloric acid was added thereto with stirring to adjust the pH of the reaction mixture to about 2 (deposit solids). Furthermore, a saturated aqueous solution of sodium hydrogencarbonate was added to adjust the pH of the mixture to about 4. Insoluble solids were collected by filtration, washed several times with water and air-dried to obtain 1.06 g (yield: 90.6%) of the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[C:30]([C:34]1[C:39]([F:40])=[C:38]([S:41][CH3:42])[N:37]=[C:36](Cl)[N:35]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:30]([C:34]1[C:39]([F:40])=[C:38]([S:41][CH3:42])[N:37]=[C:36]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[N:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CSc1nc(Cl)nc(C(C)(C)C)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Temperature: 150 °C
Yield: 26.8 %

Procedure:
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.50 mmol), 4-tert-butyl-2-chloro-5-fluoro-6-thiomethoxypyrimidine, 40a, (0.12 g, 0.50 mmol) in 1,2-dimethoxyethane (3 mL) and aqueous Na2CO3 (0.75 mL of 2 M solution, 1.5 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). The reaction mixture was degassed for an additional 15 minutes. The mixture was heated in a microwave at 150° C. for 20 minutes. Ethyl acetate (15 mL) was added. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0%-100% EtOAc/hexanes) to afford the desired product, 40b (47 mg).
Reaction SMILES: [CH3:1]/[C:2](/[O:8][Si](C)(C)C)=N\[Si](C)(C)C.N1C=[CH:19][C:17](=[O:18])NC1=O.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CO.CC[O:37][C:38]([CH3:40])=[O:39]>C(#N)C.O>[CH3:1][C:2]([CH2:19][C:17]([CH2:40][C:38]([OH:37])=[O:39])=[O:18])=[O:8]
Reactant: CCOC(C)=O
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,O-Bis(trimethylsilyl)acetamide (BSA, 54.7 mL, 224 mmol) was added to a stirred suspension of uracil (10.2 g, 90.7 mmol) and Compound 54 (31.1 g, 60.4 mmoles) in dry acetonitrile (300 mL). After stirring at rt for 30 min a clear solution was observed, and the reaction was cooled to 0 OC under nitrogen. Trimethylsilyfluoromethanesulfonate (TMSOTf, 21.9 mL, 121 mmol) was added and after the reaction was stirred at rt for 15 min, it was transferred to a preheated oil bath at 80° C. After stirring for 4 h at 80° C., the reaction was cooled to rt and MeOH (20 mL), EtOAc (250 mL) and H2O (400 mL) were added. The organic phase was then sequentially washed with sat. NaHCO3, brine, dried (Na2SO4) and concentrated to provide the crude triacetate. TLC(Rf=0.60, 80% EtOAc/hexanes). LCMS (Method DRHI), m/z=567.1 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:72](NCC4C=CC=CN=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH3:102][N:103]1[CH:107]=[C:106]([CH2:108][NH2:109])[N:105]=[CH:104]1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:109][CH2:108][C:106]4[N:105]=[CH:104][N:103]([CH3:102])[CH:107]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: Cn1cnc(CN)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)NCc6cn(C)cn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with C-(1-methyl-1H-imidazol-4-yl)-methylamine. MS (ES+) m/e 7652.53 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][O:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-fluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56,
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-trifluoromethylphenol (20.00 g) was dissolved in chloroform (160 mL), and triethylamine (34.0 mL) and acetic anhydride (12.4 mL) were added to the solution, and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (23.76 g) as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Br-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:20]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccccc1N
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of methyl anthranilate (10.0 g, 66 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to -5° C. using an ice-bath. Bromoacetyl bromide (13.32 g, 5.8 mL, 66 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of the bromide was completed, the solution was warmed to rt, stirred overnight and then the resulting solution was slowly poured into 500 mL of ice-water, causing a white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.4 g (91%) of the title compound as a white solid, mp 86°-87° C.: 1H NMR (DMSO-d6) δ11.07 (s, 1H), 8.24 (dd, J=8.4, J=1.2, 1H), 7.94 (dd, J=8.0, J=1.6, 1H), 7.64 (dt, J=8.8, J=1.6, 1H), 7.24 (dt, J=8.4, J=1.2, 1H), 4.23 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-d6) δ167.26, 165.02, 138-82, 133.97, 130.62, 123.91, 121.13, 118-09, 52.46, 30.34; MS (EI, m/z) 271 (M+).
Reaction SMILES: C(S[C:4]1[N:8]2[C:9]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)C>[Ni].C(O)C>[C:13]1([C:9]2[N:8]3[CH:4]=[N:5][CH:6]=[C:7]3[CH:12]=[CH:11][CH:10]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCSc1ncc2cccc(-c3cccc4ccccc34)n12
Agent: [Ni]
Solvent: CCO
Product: c1ccc2c(-c3cccc4cncn34)cccc2c1

Procedure:
Raney Nickel suspension (1 mL, Fluka Cat. No. 83440) is added to a solution of the title D compound, 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1,5-a]pyridine (268 mg, 0.88 mmol) in ethanol (15 mL) and heated at reflux overnight. Additional Raney Nickel (1 mL) is added, and the reaction mixture is heated at reflux for three days further, until MS showed complete disappearance of the starting material. The catalyst is filtered off and washed with ethanol. The combined filtrates are concentrated under reduced pressure. The residue is purified by flash column chromatography on silica using ethyl ether as the eluant to yield 5-naphthalen-1-yl-imidazo[1,5-a]pyridine as an amber film. The hydrochloride salt is prepared in acetone by addition of an ethereal solution of HCl (1.2 eq.). The resulting precipitate is re-crystallized from acetonitrile to yield 5-naphthalen-1-yl-imidazo[1,5-a]pyridine hydrochloride (m.p.222-223° C.): 1H-NMR, (MeOH-d4) δ 8.71 (s, 1H), 8.21 (d, J=8.1, 1H), 8.16 (s, 1H), 8.13 (d, J=16.3, 1H), 8.04 (d, J=17, 1H), 7.98-7.70 (m, 2H), 7.61 (dt, J=5.6,1.2, 1H); 7.53-7.40, m, (3H); 7.28 (d, J=7.7, 1H); 13C-NMR (MeOH-d4) δ 135.8, 135.53, 132.84, 132.68, 131.96, 130.34, 130.13, 129.81, 129.11, 128.15, 127.04, 126.18, 125.60, 124.79, 120.93, 119.43, 116.50, 112.96; MS (M+1)+ 245.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=S(=O)(O)Cl
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
94.0 g (0.5 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene were stirred into 100 ml of chlorosulfonic acid at 20° C. within 30 min. The reaction solution was maintained at 60° C. for 1 hour, cooled to room temperature and then poured into 1.5 1 of ice and extracted with ether. The organic phase was washed to neutrality with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yielded 55.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-sulfonyl chloride of melting point 71°-74° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.O>ClCCCl>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][C:2]([CH3:1])([CH3:16])[C:3]2=[O:5])=[CH:8][C:9]=1[CH3:15]
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: O
Product: COc1cc2c(cc1C)CC(C)(C)C2=O
Reaction time: 2 h

Procedure:
A mixture of 9.0 g of 2,2-dimethyl-3-(4-methoxy-3-methylphenyl)propanoic acid and 20 mL of oxalyl chloride was prepared and allowed to stir for 2 hours. The volatiles were then removed by evaporation under reduced pressure. The residue was dissolved in 30 mL of carbon disulfide and the solution was added with stirring to a mixture of 7.4 g of aluminum chloride and 30 mL of carbon disulfide. The mixture was allowed to react for 2 hours and was then diluted with 200 mL of 1,2-dichloroethane. Water was added slowly with stirring and, after 2 hours, the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain the title compound as a colorless liquid boiling at 90°-95° C. under 1 mm Hg (133 Pascals) pressure.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][OH:8])[CH2:4][OH:5].[CH3:9][C:10]1C=CC(S(O)(=O)=O)=C[CH:15]=1.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:10]1([CH3:15])[O:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCC(CO)CO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCO)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 989.3 %

Procedure:
A solution of compound 31 (160 g, 1.30 mol) and 2,2′-dimethoxypropane (207 g, 1.90 mol) in dry acetone (800 mL) was added p-TsOH (92 g, 0.053 mol) under N2 and stirred at RT for 12 h. To this was added triethylamine drop-wise to neutral pH and then concentrated under vacuum below 35° C. The crude residue was purified by column chromatography over neutral alumina (12% ethyl acetate in pet ether) to give the title compound (84 g, 39%). TLC: Pet ether/EtOAc, 1:1, Rf=0.2
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:20]2[CH2:11][C:5]3[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.200 g, 0.56 mmol), 4-chloro-benzylamine (0.7 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-chloro-benzyl)-7-iodo-2,3-dihydro-isoindol-1-one (0.084 g, 39%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.16 (s, 2H), 4.75 (s, 2H), 7.16-7.40 (m, 6H), 7.92 (d, 1H). GC-MS: m/z 367 (M)+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.N[C:10]([NH2:12])=[O:11].[N+:13]([C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N:7]([C:6]1[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:1]=1)=[O:11].[N+:13]([C:16]1[CH:21]=[CH:20][C:10]([NH2:12])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(N)=O
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(N=O)cc1
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
To achieve the above object, there is provided a method of preparing p-phenylenediamine including the steps of: reacting urea and nitrobenzene with a base in the presence of a polar solvent to yield 4-nitrosoaniline and 4-nitroaniline; and subsequently, diluting the resulting mixed solution in an alcohol and performing hydrogenation using a catalyst.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O.C(Cl)Cl.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])=[CH:6][CH:5]=1
Reactant: Nc1cnccc1CCOc1ccc([N+](=O)[O-])c2ccccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1cnccc1CCOc1ccc(N)c2ccccc12
Yield: 96.8 %

Procedure:
A solution of 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-3-amine (17) (700 mg, 2.263 mmol) in a mixture of MeOH (50 mL), EtOAc (25 mL), and DCM (25 mL) was passed through a Thales H-cube (10% Pt/C 30 mm, 1.0 mL·min−1, at 40° C., full hydrogen mode). The solvent was removed in vacuo to give 4-(2-(4-aminonaphthalen-1-yloxy)ethyl)pyridin-3-amine (18) as a brown solid (612 mg, 92%). m/z 280 (M+H)+ (ES+).