Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 75 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 60° C. for 72 hours yielding tert-butyl 1-(4-methoxy-2-nitrophenyl)piperidin-4-ylcarbamate (75%). LCMS (m/z): 352.1 (MH+); LC Rt=3.22 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]2[N:47]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:46]3[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=3[N:44]=2)[CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[C:3]([C:8]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)[C:46]4[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=4[N:44]=3)[CH2:38][CH2:37]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nccnc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: Nc1nccnc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred mixture of 2.1 parts of 3-amino-2-pyrazinecarboxylic acid, 2.8 parts of N,N-dibutylbutanamine and 195 parts of dichloromethane were added 3.83 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 15 minutes at room temperature, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine were added and stirring was continued for one hour. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The latter was decanted and the residue was purified by column-chromatography over slica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 2.8 parts (38%) of 3-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamide; mp. 156.9° C. (compound 113).
Reaction SMILES: [C:1]1([C:7]2[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23](C)([O-])[CH3:24].[K+].BrCC=C.O>CC(O)C>[CH2:24]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([O:12][CH2:13][CH2:14][CH3:15])[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:9]1)[CH:23]=[CH2:22]
Reactant: CC(C)(C)[O-]
Reactant: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: C=CCBr
Product: C=CCn1nc(-c2ccccc2)c(OCCC)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
3,5-Diphenyl-4-n-propoxypyrazole (9.0 g, 0.038 mole) is dissolved in 2-propanol (90 ml). Potassium t-butoxide (4.65 g, 0.042 mole) is added at room temperature and the reaction mixture stirred and heated at 50°C for 3 hours. It is then cooled to room temperature and 3-bromoprop-1-ene (5.53 g, 0.046 mole) is added dropwise. A white solid forms. Stirring is continued at room temperature overnight, the mixture is then poured into water and extracted with chloroform. The chloroform layer is washed with water (3 × 150 ml) and stripped under vacuum. The residual oil is purified by dry column chromatography (silica gel/toluene). The toluene solution is stripped under vacuum to afford 6.64 g (55%) product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][Si](C)(C)C)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[CH:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C#C[Si](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A solution of 5.23 g (19.8 mmol) of 4-methyl-2'-trimethylsilylethynyl-1,1'-biphenyl in 60 mL of methanol was treated with 6 mL of 1.25N aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 30 minutes and evaporated under vacuum. The residue was extracted with ether. The combined ether extracts were washed with water, dried over magnesium sulfate and evaporated under vacuum. The residue was purified by chromatography over silica gel, eluting will hexane, to yield 2.52 g (13.1 mmol, 66%) of the product. FAB-MS: calculated from C15H12 192; found 191 (M-1). 1H NMR (200 MHz, CDCl3): 2.40 (s, 3H), 5.26 (s, 1H), 7.3 (m, 8H).
Reaction SMILES: O[C@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Mn]([O-])(=O)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[N:25]([C@@H:2]1[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C[C@@H](O)CN1
Agent: O=[Mn](=O)(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To an ice cooled solution of (R)-(+)-4-hydroxy-2-pyrrolidinone (25.0 g, 247 mmol) in dichloromethane (300 mL) was added triethylamine (17.0 g, 168.7 mmol) and methane sulfonyl chloride (21 mL, 272 mmol) dropwise. The solution was stirred at ambient temperature for one hour. The reaction was monitored via TLC (100% ethyl acetate using permanganate stain). The solution was then condensed under reduced pressure to give a solid. The solid was diluted with DMF (300 mL) followed by the addition of sodium azide (48.24 g, 742 mmol). The solution was heated to 60° C. for 3 hours. The reaction was monitored via TLC (100% ethyl acetate using permanganate stain). The solution was then condensed under reduced pressure and the resultant oil purified via silica gel chromatography (50-80% acetate/hexanes followed by 12% methanol/dichloromethane) to afford the title compound (10.2 g, 32%). 1H—NMR (CD3OD) δ 4.43 (m, 1H), 3.71 (dd, 1H), 3.34 (m, 1H), 2.75 (dd, 1H), 2.29 (dd, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(CO)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OCc1ccccc1
Yield: 105.5 %

Procedure:
Thionyl chloride (64 ml) was added over 10 minutes to a stirred solution of the above alcohol in dichloromethane (500 ml). After 20 minutes the mixture was evaporated to dryness, in vacuo, toluene (2×75 ml) added, and evaporation in vacuo repeated to give crude 3-benzyloxy-4-methoxy-benzyl chloride (97.85 g, 105.5%). The chloride (353 mmole) was dissolved in acetone, (400 ml) treated with sodium thiocyanate, (57.22 g ,706 mmole) homogenized and heated under reflux for 1.5 hours. The solid was filtered off at room temperature and the solvent evaporated in vacuo. The residue was suspended in water (600 ml) to give a solution of pH 2, and neutralized with sodium bicarbonate solution. After crystallization the solid was collected, dried, dissolved in dichloromethane (300 ml) , dried (Na2SO4), treated with charcoal, filtered and evaporated to dryness. The residue was crystallized from petroleum ether (400 ml) to give 3-benzyloxy-4-methoxy-benzyl thiocyanate (95.65 g, 95.0%), mp 70-74° C. The thiocyanate (335 mmole) was heated under reflux in n-valeronitrile (280ml) for 2 hours and evaporated to dryness to give 98.4 g of crude product. This was dissolved in THF (200 ml) and treated with 32% aqueous ammonia solution (101 ml) at room temperature. After 3 hours the thiourea was collected at 10° C. and washed with diethyl ether to give 1-(3-benzyloxy-4-methoxy-benzyl)-2-thiourea (63.08 g, 62.2%), mp 179-181° C. The filtrate was evaporated to dryness and the residue crystallized from dichloromethane to give 11.51 g (11.3%) as a second crop.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:14]=[C:13]([C:15](Cl)=[O:16])[O:12][N:11]=1)[CH3:9].O.Cl>ClCCl>[CH2:8]([C:10]1[CH:14]=[C:13]([C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[O:12][N:11]=1)[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCc1cc(C(=O)Cl)on1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(=O)Nc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
11.7 g of aniline are added dropwise to 10.0 g of 3-ethylisoxazole-5-carbonyl chloride in 150 ml of dichloromethane, while cooling with ice. The mixture is stirred overnight at room temperature, water and concentrated hydrochloric acid are added and the organic phase is separated off, washed with sodium bicarbonate solution and evaporated down to give 11.8 g of 3-ethylisoxazole-5-carboxanilide as colorless crystals of melting point 122°-124° C.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([N:13]([CH3:22])[N:14]([CH3:21])[C:15](=[O:20])[CH2:16]2)=[N:11][C:10]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:22][N:13]1[C:12]2=[N:11][C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([OH:8])[C:18](=[O:19])[N:17]2[CH2:16][C:15](=[O:20])[N:14]1[CH3:21]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N(C)N2C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Yield: 97.6 %

Procedure:
A solution intermediate 21, ethyl 7-benzyloxy-1,2-dimethyl-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.306 g, 0.82 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (60 ml),at 25° C., over 10% palladium on activated carbon (50 mg) and was treated with 1 atm of hydrogen for 1 h to give 0.226 g (97% yield) of the title amide as a white solid after recrystallization from ethyl acetate. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.47 (3H, t, J=7.1 Hz, CH3), 3.28 (3H, s, NCH3), 3.36 (3H, s, NCH3), 4.51 (2H, q, J=7.1 Hz, OCH2), 4.68 (2H, s, CH2), 10.60 (1H, s, OH). MS (ESI+) m/z 283 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[N:13][C:12]([CH3:17])=[CH:11][CH:10]=2)=[O:5])C.Cl>[OH-].[K+]>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[N:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccc(C)nc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc2ncc(C(=O)O)c(O)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
The suspension of 4-hydroxy-6-methyl-[1,5]naphthyridine-3-carboxylic acid ethyl ester (4.15 g, 17.87 mmol) in 10% KOH (40 mL) was stirred at room temperature for 3.5 hrs. 3 N HCl was added to adjust the pH to 7. The solid was collected by filtration to give 4-hydroxy-6-methyl-[1,5]naphthyridine-3-carboxylic acid (2.58 g, 72%). HR-ES (+) m/e calcd for C10H8N2O3 (M+H) 205.0608. found 205.0608.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[N:6]=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nc1nnnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)Nc1nnnn1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a suspension of 1.3 g of 7-chloro-5-phenyltetrazolo[1,5-a]quinazoline in 100 ml of ethanol was added 0.2 g of sodium borohydride. The mixture was stirred at room temperature for 1 hour and then poured into 200 ml of water. The resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give 0.98 g of 7-chloro-4,5-dihydro-5-phenyltetrazolo[1,5-a]quinazoline as colorless needles, m.p. 260°-261° C. (decomp.).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][N:11]2[C:12](=[O:22])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[Cl:21])=O)(C)(C)C.Cl>>[ClH:21].[Cl:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[C:12](=[O:22])[N:11]1[CH2:23][CH2:24][NH:8][CH2:9][CH:10]12
Reactant: COc1cc(Cl)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: Cl
Product: COc1cc(Cl)c2c(c1)C1CNCCN1C2=O
Reaction time: 0.25 h
Yield: 172.9 %

Procedure:
To (±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one (20 mg, 0.06 mmol) was added concentrated hydrochloric acid (1 mL). After 15 min, the resulting solution was concentrated, diluted with water, and lypholized to give (±)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt as an off-white solid (15 mg, 91%). MS (ESI) 253.1, 255.1 (M−Cl)
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:15][C:12]1[N:11]=[C:10]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:17])[C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1OCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1O
Reaction time: 12 h
Yield: 55.9 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)picolinamide (50 mg, 0.11 mmol) in CH2Cl2 (5 mL) was added BBr3 (1.5 mL) dropwise at −78° C. under N2. The mixture was allowed to room temperature and stirred for another 12 hours. Then CH3OH was added and the mixture was adjusted to pH=7 by saturated K2CO3. The mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE:EtOAc=5:1) to afford the product of 6-bromo-N-(4-fluorobenzyl)-3-hydroxypicolinamide (20 mg, yield: 57%). 1H-NMR (CDCl3, 400 MHz) δ 12.04 (s, 1H), 8.02 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.24˜7.28 (m, 2H), 7.15 (d, J=8.8 Hz, 1H), 6.96˜7.00 (m, 2H), 4.52 (d, J=6.4 Hz, 2H). MS (M+H)+: 325/327.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[C:27]([F:30])([F:29])[F:28])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[C:27]([F:29])([F:30])[F:28])[CH3:18]
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1C(F)(F)F

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.26 g, 1.13 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (39e) (117.5 mg, 0.56 mmol), WSC hydrochloride (0.38 g, 1.98 mmol) and HOBT (76 mg, 0.56 mmol), to obtain 0.19 g of the title compound as a white foamy substance (79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:11][C:10]([CH3:12])=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[Br:13]Br>ClCCl>[Br:13][C:9]1[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([Cl:1])[C:3]=2[NH:11][C:10]=1[CH3:12]
Reactant: BrBr
Reactant: Cc1nc(Cl)c2[nH]c(C)cc2n1
Solvent: ClCCl
Product: Cc1nc(Cl)c2[nH]c(C)c(Br)c2n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2,6-dimethyl-5H-pyrrolo[3,2-d]pyrimidine from example A7 (10.90 g; 60.00 mmol) is dissolved in dichloromethane (120 mL). The stirred mixture is cooled to −10° C. Br2 (3.08 mL; 60.00 mmol) dissolved in dichloromethane (20 mL) is added dropwise within 25 minutes. The re-suiting precipitate is collected by suction filtration, suspended in Na2SO3 (5% solution) (100 mL) and is stirred for 30 minutes at ambient temperature. After filtratrion the product is dissolved in acetonitrile (1000 mL), refluxed for one hour and filtered while still hot. The solvent is removed under reduced pressure until the product starts to precipitate. Precipitation of the product is completed by addition of cyclohexane and cooling to 0° C. for several hours. The solid is collected by suction filtration, washed with cyclohexane and dried in vacuum at 50° C. over night to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(O[CH2:13][CH3:14])C>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:6][C:7]3[C:14]([CH:13]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCOCC
Product: Cc1cc(C)cc(C2=Cc3ccccc3C2)c1

Procedure:
A 3-neck 500-mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 1.86 g (77 mmol) of Mg turnings and 15 mL of anhydrous diethyl ether. Slow addition of a solution of 9.9 g (53 mmol) of 3,5-dimethyl-bromobenzene in diethyl ether (60 mL), followed by refluxing for 1 hour, gave an orange solution of the aryl Gnrgnard reagent. The solution was cooled to room temperature, filtered over a plug of Celite and the solvent was removed in vacuo from the filtrate. Toluene (30 mL) was added and the solution cooled to 0° C. whereupon a solution of 2-indanone-(5.67 g, 43 mmol) in toluene (50 mL) was added dropwise to give an orange slurry. This mixture was warmed to room temperature and stirred for an additional 9 hours. After cooling to 0° C., it was quenched with 100 mL of water. Hexane (150 mL) was added and the reaction mixture neutralized with 5M HCl. The organic layer was separated, and the aqueous layer was extracted with two 40-mL portions of hexane. The combined organic layers were washed with two 40-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed in vacuo yielding 2-(3,5-dimethyl)phenylindanol as a very viscous oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([OH:22])(=[O:21])[CH2:18][CH2:19][CH3:20]>>[C:17]([O:22][CH2:12][C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:14])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)O
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Product: CCCC(=O)OCC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-phenylphenacyl bromide are reacted with 5 grams of butyric acid to obtain 4-phenylphenacyl butyrate, m.p. 82° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[C:21](O)(=[O:25])[C:22](O)=[O:23]>Cl>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[NH:18][C:22](=[O:23])[C:21]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1NCc1ccccc1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of 0.5 g (2.1 mmol) N-benzyl-2-amino-4-nitroaniline and 0.55 g (4.4 mmol) oxalic acid dihydrate in 30 ml 4N hydrochloric acid was refluxed for 5 h. After cooling to 25° C. the product was filtered off and washed with water. The crude product was recrystallized (dimethylformamide-water), washed with 10 ml water, 5 ml ethanol and 5 ml ether to give 0.3 g (49%) 1-benzyl-6-nitroquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): 292.2° C. 1H-NMR (DMSO-d6): 12.4 (1H, broad s), 8.2-7.0 (8H, m), 5.4 (2H, s).
Reaction SMILES: C(=O)([O-])N.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:6]1([N:5]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]2[NH2:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Fc1ccccn1
Reactant: Nc1ccccc1
Agent: NC(=O)[O-]
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: NC1C=CC=CN1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A substituted aniline was N-protected with a formyl, Boc or similar amide or carbamate protecting group using a standard method. Subsequently, this N-protected aniline derivative was dissolved in DMF (under N2), cooled to 0° C. and added NaH (1.1 eq). After stirring for 30 min at rt, 2-fluoropyridine was added to the reaction mixture and stirring was continued at 70° C. for 1-3 days. After cooling to rt, aqueous saturated NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was purified by preparative LC-MS or by column chromatography to give the desired N-protected N-phenyl-2-aminopyridine. After a reaction step to remove the N-protecting group, using a standard method, the obtained phenyl-pyridin-2-yl-amine was dissolved in acetonitrile (under N2) in a closed vial and added the required halide for the N-alkylation. The reaction mixture was then heated to 100-150° C. for 30-720 min using MW irradiation. After cooling to rt, the crude product could be isolated upon aqueous basic work-up and subsequently purified by preparative LC-MS or, alternatively, by column chromatography and/or recrystallization to give the desired N,N′-disubstituted 2-aminopyridine.
Reaction SMILES: [C:1]([C:4]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:17]1[C:4]2[C:1](=[O:3])[S:11][C:7]([C:8]([OH:20])=[O:13])=[CH:6][C:5]=2[CH:14]=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: COc1cccc(C=C2SC(=S)NC2=O)c1C(=O)O
Agent: Cl
Agent: [Na+]
Product: COc1cccc2cc(C(=O)O)sc(=O)c12

Procedure:
A solution of the benzylidenerhodanine of Example 10 in 46 ml. of 15% NaOH is refluxed for 0.75 hour, cooled, and poured into dilute HCl. The resulting tan precipitate is collected and air-dried. Two recrystallizations from methanol (charcoal) give 8-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as a pale yellow solid, m.p. 275° (dec.).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2)c(-c2ccccc2)n1
Yield: 34.4 %

Procedure:
6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (130 mg, 34%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-dichlorophenylboronic acid (0.42 g, 2.19 mmol) according to the general procedure of Example 1.