Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CS(C)=O>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:25]4[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CS(C)=O
Product: CC(=O)NC1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and N-pyrrolidin-3-yl-acetamide with DMSO as a solvent. 1H NMR (400 MHz, DMSO-d6): δ 8.73-8.76 (m, 1H), 8.17-8.18 (m, 1H), 7.72-7.75 (m, 1H), 7.49-7.56 (m, 2H), 6.96-6.99 (m, 1H), 4.34-4.35 (m, 1H), 3.71-3.76 (m, 1H), 3.59-3.63 (m, 2H), 3.38-3.40 (m, 1H), 3.22-3.25 (m, 2H), 2.15-2.20 (m, 1H), 2.01-2.07 (m, 2H), 1.73-1.94 (m, 9H), 1.29-1.32 (m, 2H). m/z: 465.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:12]([CH3:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)=O
Product: CC(C)Nc1ccc(F)cc1
Yield: 90 %

Procedure:
A process according to claim 1, wherein the N-alkyl-arylamine (I) is of the formula ##STR31## 4-fluoro-nitrobenzene is employed as the nitroarene and acetone as the carbonyl compound, the reaction mixture consisting of the stated catalyst and the reactants, wherein the acetone is employed in excess and constitutes the sole diluent for the reaction, the 4-fluoro-N-isopropyl-aniline of the above formula (3) being produced in a yield of at least 90% of theory.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].N>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h
Yield: 100.9 %

Procedure:
75 g of 1-nitroanthraquinone (98.5 % strength) are heated to 180° C in 145 ml of water. Thereafter, a cold solution of 14.6 g of NH4Cl in 240 ml of 25 % strength aqueous ammonia is pumped into this mixture within 5 minutes. The temperature is kept constant for 1 hour, the pressure rising during this period to 51 bar. After cooling and releasing pressure, the product is filtered off by suction and washed with water. Both filtrate and washing water (1 liter) are slightly yellow in color, E47010 cm = 13.0. 66.7 g of 95.2 % pure 1-aminoanthraquinone (97.5 % of theory) are obtained. The product still contains about 1.0% of 1-nitroanthraquinone.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 11A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.08 (d, J=8.42 Hz, 1H) 7.98 (d, J=1.87 Hz, 1H) 7.60 (dd, J=8.58, 1.72 Hz, 1H) 4.09 (s, 3H) 3.84-3.98 (m, 1H) 3.47-3.65 (m, 1H) 2.99-3.18 (m, 1H) 2.66-2.80 (m, 2H) 2.44-2.62 (m, 2H) 2.27-2.44 (m, 1H) 1.92-2.04 (m, 1H) 1.80-1.92 (m, 1H) 1.67-1.78 (m, 1H) 1.44-1.64 (m, 2H) 1.14 (s, 3H). MS: (M+H)+=378.
Reaction SMILES: [CH2:1]([C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4])[CH3:2].C(O)(=O)C(O)=O.C(C(C1(C2C=CC=CC=2SC2C=CC=CC=2)CC[N:38](C)CC1)=O)C.C(=O)([O-])[O-].[K+].[K+].N#CBr>C(Cl)(Cl)Cl.C(O)C>[C:11]([N:8]1[CH2:7][CH2:6][C:5]([C:3]([CH2:1][CH3:2])=[O:4])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)#[N:38]
Reactant: CCC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C)CC1
Agent: N#CBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C#N)CC1

Procedure:
A solution of 3.2 g of 4-ethylcarbonyl-1-methyl-4-(2-phenylthiophenyl)piperidine, free base of Example 5 in 300 ml of chloroform is added portionwise over a 10 minute span to a refluxing mixture of 7.5 g of potassium carbonate and 2.0 g of cyanogen bromide in 30 ml of chloroform. After total addition, stirring is continued at reflux for two additional hours. Thereafter, the mixture is filtered and the filtrate is concentrated to dryness, leaving an oil residue. The residue is taken up in about 50 ml of ethyl alcohol and the alcoholic solution is heated on a steam bath for 5-10 minutes before evaporating off the solvent. The resulting oil solidifies on standing and the solid is recrystallized from a benzene-hexane mixture to provide 1-cyano-4-ethylcarbonyl-4-(2-phenylthiophenyl)-piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N+:6]([O-])[CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(F)c[n+]1[O-]
Product: COC(=O)c1ccc(F)c(Cl)n1
Temperature: 0 °C
Yield: 79 %

Procedure:
5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (100 mg, 0.584 mmol) was dissolved in POCl3 (2 ml), and then heated at reflux under nitrogen stream for 4 hours. The resulting reaction liquid was slowly added to ice (15 g), and then extracted with MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 88 mg of white solid (79%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(O)C>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 30.3 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.35 g.), conc. hydrochloric acid (0.39 g.), ethanol (5.3 ml.) and tetrahydrofuran (8 ml.) was stirred at room temperature for 4.5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in an aqueous solution of sodium bicarbonate, treated with activated charcoal and filtered. The filtrate was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.1 g.).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[CH:33][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:23][CH:24]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[O:26]([CH2:25][C:22]1[NH:23][CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:34][CH:33]=3)=[CH:15][CH:16]=2)[N:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(COc2ccc(Oc3ccc(-c4c[nH]c(COc5ccccc5)n4)cc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 24 h

Procedure:
In a 100 ml reactor, 138 mg of 4-{4-[4-(benzyloxy)phenoxy]phenyl}-2-(phenoxymethyl)-1H-imidazole (0.0003 mol) in 10 ml of ethanol with a catalytic quantity of palladium adsorbed on carbon (10% by mass), are hydrogenated for 24 hours under a hydrogen pressure of 4 bars. The reaction medium is filtered on a millipore filter then rinsed with ethanol and evaporated to dryness. The residue is triturated with diethyl ether and the mixture is stirred in diethyl ether and the solid is filtered. The product obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 2-8 to 5-5). After washing with diethyl ether, a white-coloured powder is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:4]=2[O:3]1.CN(C=O)C.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)Cl>[Br:27][C:10]1[C:11]([CH3:13])=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:7](=[O:8])[NH:6][C:5]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1Br)NC(=O)C(C)(C)O2
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of Compound 1A (4.24 g, 22.2 mmol) in 150 mL of chloroform was treated with 5 mL of dry DMF followed by 4.4 g (24.4 mmol) of NBS at room temperature. After 4 hours, the reaction was quenched with 150 mL of a saturated sodium thiosulfate solution. The aqueous layer was extracted with chloroform and the combined organic layers were dried with magnesium sulfate, filtered, and excess solvent removed on the rotary evaporator. The crude product was purified via silica gel chromatography (5% EtOAc/Hexanes) to yield 3.48 g of brominated product (58%). MS (electrospray): mass calculated for C11H12BrNO2, 269.01; m/z found 268, [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.CS(O)(=O)=O.[CH2:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[OH:1][C:2]1[C:7]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=CCCCCCCCCCC
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 160 °C
Reaction time: 96 h

Procedure:
Using the general procedure of Example 1, 112 grams of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole, 33 ml of methanesulfonic acid and 444 ml (2 moles) of a mixture of tetracosenes (prepared by the dimerization of n-dodecene) are heated at 160° C.; for 96 hours. The reaction mixture is cooled and the product isolated by the general procedure described in Example 1. The excess hydrocarbons are removed by distillation at 190° C./0.04 mm. The above-named product is obtained in a yield of 103.6 grams as a yellow liquid. The liquid still contained inert hydrocarbon diluents which are removed by flash chromatography using silica gel and heptane/toluene 75/25 to give a pure product in a yield of 15 grams as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:20])[CH3:17]
Reactant: CCN(CC)CCCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)CCCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 64 h

Procedure:
A solution of 6-Amino-1-(3-diethylamino-propyl)-3,4-dihydro-1H-quinolin-2-one (0.058 g, 0.211 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.120 g, 0.421 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1: 10-9). The product 7 was dried under high vacuum. Yield: 35 mg of yellow solid (44%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.90 (br s, 2H), 4.03-3.99 (m, 2H), 2.90-2.85 (m, 2H), 2.77-2.62 (m, 8H), 2.03-1.93 (m, 2H), 1.15 (t, J=7.2 Hz, 6H). MS (ESI): 385.2 (M+1). ESI-HRMS calculated for C21H29N4SO2 (MH+): 385.2056, Observed: 385.2040.
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([C:29]([F:32])([F:31])[F:30])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=1.[F:35][C:36]([F:42])([F:41])[CH2:37][C:38](O)=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[F:35][C:36]([F:42])([F:41])[CH2:37][C:38]1[NH:2][C:3]2[C:8]([CH:9]=1)=[C:7]([C:29]([F:30])([F:31])[F:32])[C:6]([C:33]#[N:34])=[CH:5][CH:4]=2
Reactant: N#Cc1ccc(N)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C(F)(F)F
Reactant: O=C(O)CC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
A mixture of {[6-amino-3-cyano-2-(trifluoromethyl)phenyl]methyl}(triphenyl)phosphonium bromide (0.50 g, 0.92 mmol), 3,3,3-trifluoropropanoic acid (0.175 g, 1.40 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (2.60 g, 4.10 mmol, 50% in EtOAc) and DIEA (0.65 mL, 3.70 mmol) in THF (25 mL) was stirred at ambient temperature for 6 h. The mixture was concentrated and then diluted with anhydrous DMF (15 mL) and stirred at 100° C. for 18 h. The reaction was poured into water (100 mL) and extracted with Et2O (2×60 mL). The combined organic portions were washed with sat'd NaHCO3 (50 mL) and brine (50 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 30% EtOAc in hexanes) to afford 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.189 g, 70%) as a pale yellow solid:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.CN(C)C=O.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(#N)C>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:25](=[O:26])[O:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [4-(1H-tetrazol-5-yl)phenyl]amine (0.97 g, 0.006 mol, prepared in sequence by the procedures described by W. G. Finnegan et al., J. Amer. Chem. Soc, 1958, 80, 3908 and McManus and Herbst, J. Amer. Chem. Soc,, 1959, 24, 1044) in acetonitrile (30 mL), dimethylformamide (7 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° C. was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 1M HCl, resulting in separation of product insoluble in either phase. This was collected, triturated with wet ether and dried in vacuo overnight to yield 1.37 g of [4-(1H-tetrazol-5-yl)phenyl]carbamic acid, 4-nitrophenyl ester, m.p. >260° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:0.2), Rf =0.63; 1H-NMR (DMSO-d6 ) δ7.6 (d, J=8.8 Hz, 2H), 7.7 (d, J=8.8 Hz, 2H), 8.1 (d, J=8.8 Hz, 2H) 8.3 (d, J=8.8 Hz, 2H); 13C-NMR (DMSO-d6) δ150.6, 144.7, 140.9, 128.0, 125.3, 123.0, 118.9, 118.2. M.S., (M+H)+ at 327, M.W. 326.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=2[O-:11])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Br)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc([N+](=O)[O-])cc[n+]2[O-])CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a solution of 2-bromo-4-nitropyridine N-oxide (12 g), which is prepared according to the method disclosed in J. Org. Chem., 21, 1077 (1956), in ethanol (300 ml) are added 4-piperidinecarboxylic acid ethyl ester (22 g) and triethylamine (11.6 ml), and the mixture is stirred at 80° C. for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water, and the solvent is evaporated under reduced pressure to give the title compound (18 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:10](=[N:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:19])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:20][N:16]3[C:15]4[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[N:11][C:10]=4[CH:9]=[C:8]3[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2[nH]c(-c3nc(Cl)ccc3O)cc2n1
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(cc3n2COc2ccc(Cl)nc2-3)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a stirring solution of 6-chloro-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol (200 mg, 0.727 mmol) and Cs2CO3 (472 mg, 1.45 mmol) in DMF (15 mL) was added chloroiodomethane (192 mg, 1.09 mmol) in DMF (2 mL) dropwise at 100° C. under N2. The mixture was stirred at 100° C. for 1 hour. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using Pre-TLC to provide 2-chloro-10-methoxy-6H-pyrido[2,3-e]pyrido[2′,3′:4,5]pyrrolo[1,2-c][1,3]oxazine (110 mg, yield: 52%). 1H-NMR (CDCl3, 400 MHz) 7.44 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.81 (s, 2H), 3.95 (s, 3H). MS (M+H)+: 288/290.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:21]2[CH:31]=[C:25]3[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]3[C:23](=[O:32])[N:22]=2)=[CH:10][C:11]=1[F:12]
Reactant: OCc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 3-(bromomethyl)-2,4-dichloropyridine (1.41 g, 5.86 mmol) in anhydrous ethanol (20 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (0.58 g, 4.09 mmol) and triethylamine (0.65 g, 6.43 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to precipitate the product. The white solid was filtered and washed with water and ether to provide 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.795 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.31 (s, 3H), 4.68 (s, 2H), 6.04 (bs, 1H), 7.67 (d, J=5.3 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H); M+302.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]CC3C=CC=CC=3)[CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]=1[CH3:32])=[O:8]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]=1[CH3:32])=[O:8]
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(OCc3ccccc3)ccc2n1-c1ccccc1
Solvent: CO
Product: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(O)ccc2n1-c1ccccc1
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a mixture of 5-benzyloxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid, 3,4-difluoro-benzylamide (Compound 56, 0.15 g, 0.31 mmol) in methanol (15 ml), which was degassed with argon for 10 min, was added 10% palladium on carbon (0.17 g), with continued degassing. The reaction was placed in par tube on hydrogenator and hydrogenated at 45 psi for 18 h. The reaction was then filtered, concentrated under reduced pressure and the crude product residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to yield 5-hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 29) as a solid (0.11 g, 92%).