Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:11].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[CH:12]1([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[F:11])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(F)c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-1-fluoro-3-nitrobenzene (2.0 g, 9.1 mmol), cyclopropanamine (1.26 mL, 18.2 mmol) in THF (10 mL) under N2 was heated at 60° C. for 4 days. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using hexane-EtOAc (8.5:1.5) as eluent to give N-cyclopropyl-2-fluoro-6-nitroaniline.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:27]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:28]4[N:27]=[C:26]([CH3:25])[CH:33]=[CH:32][C:29]=4[C:30]#[N:31])[CH2:35][CH2:36]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: Cc1ccc(C#N)c(N2CCNCC2)n1
Product: Cc1ccc(C#N)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 6-methyl-2-piperazin-1-yl-nicotinonitrile (CAS 622405-21-4) to give the title compound as an off-white solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 1.5 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 20 ml of N,N-dimethylformamide, 1.3 g of N-bromosuccinimide was added. The mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.9 g of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:16](C)C=O.N>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([NH2:16])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 50.0 g (260 mmol) 3-Benzo[1,3]dioxol-5-yl-acrylic acid in 300 ml tetrahydrofuran and 3.0 ml N,N-dimethyl formamide 44.5 ml (350 mmol) oxalyl chloride was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 750 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 49.5 g (99%) 3-Benzo[1,3]dioxol-5-yl-acrylamide were obtained.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][N:14]3C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][NH:14]3)[CH2:11]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(C(F)(F)F)cn3)[C@@H]1C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
xHCl. To the title compound of step A (622 mg, 1.74 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (10 mL). After 2 h, the reaction was concentrated to give the title compound of step B (507 mg) which was used without further purification. MS (ESI) mass calcd. for C12H13F3N2O, 258.1. m/z found 259.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]I)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN(C=O)C.CCOC(C)=O>[C:12]([N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 4-hydroxybenzoate (Aldrich) (0.4 g, 2.6 mmoles) 9-1 in DMF (10 ml) was treated with 2-(N-Boc-4-piperidinyl)ethyl iodide 1-4 (0.6 g, 1.77 mmoles) and CS2CO3 (1.15 g, 3.5 mmoles) with stirring at room temperature for 48 hours. The reaction mixture was diluted with EtOAc, washed with H2O, saturated NaHCO3, 10% KHSO4, brine dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to give pure 9-2. Rf 0.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccccc1
Yield: 69.8 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (100 mg), methanol (5 ml) and THF (5 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10](O)=[O:11])[CH2:7][C:6]=2[CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:32]([CH3:34])[CH3:33])C2C=CC=CC=2N=N1.CNC.O1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:32]([CH3:34])[CH3:33])=[O:11])[CH2:7][C:6]=2[CH:13]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)C1Cc2cc(Br)ccc2O1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C(=O)C1Cc2cc(Br)ccc2O1
Yield: 87 %

Procedure:
A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243 g, 1.00 mmol) (ParkWay, Cat. No. YB-162), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.464 g, 1.05 mmol) and 2.0 M dimethylamine in tetrahydrofuran (THF) (2.00 mL, 4.00 mmol) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.235 g, 87%). LCMS (M+H)+=270.0/272.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[F:21][C:22](I)([F:24])[F:23]>[Cu].CN(C)C=O>[F:21][C:22]([F:24])([F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2Br)cc1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl 2'-bromo-4-biphenylylglycolate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140°C, cooled and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl 2'-trifluoromethyl-4-biphenylylglycolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([F:72])([F:71])[F:73])=[CH:66][N:65]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)cn3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 28.9 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.200 g, 0.537 mmol), COMU (0.873 g, 1.34 mmol), DIPEA (0.173 g, 1.34 mmol) and 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.105 g, 0.591 mmol), iron powder (0.050 g) and acetic acid (5.0 mL) to afford 0.080 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 2.24 (s, 3H), 3.13 (s, 2H), 7.25-7.33 (m, 2H), 7.42 (d, J=7.5 Hz, 1H), 7.56 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.75 (s, 1H), 9.16 (m, 1H), 10.49 (s, 1H), 10.99 (s, 1H); MS [M]+: 516.06.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][N:29]=1)[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:20]>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([OH:14])=[C:8]2[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][N:29]=1)[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])=[O:20])#[N:4]
Reactant: CN(C)CCNC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccnc(-c2c(O)[nH]c3ccc(C#N)cc23)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
To a suspension of sodium hydride (0.15 g, 3.70 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added a solution of 5-cyanooxindole (0.29 g, 1.84 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 30 min under a nitrogen atmosphere. 2-Chloro-N-[2-(dimethylamino)ethyl]isonicotinamide (0.21 g, 0.92 mmol) dissolved in N,N-dimethylformamide (4 mL) was added dropwise and the mixture was stirred at room temperature for 30 min and then heated at 150° C. for 45 min. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. A 2 M aqueous HCl solution was added until pH 2 and the mixture was extracted with ethyl acetate. To the aqueous layer, a 45% aqueous NaOH solution was added until pH 11 and the suspension was extracted with ethyl acetate. The aqueous layer was concentrated in vacuo and the crude product was purified by preparative HPLC (column: Xterra, 19×300 mm, eluent: 0.05 M NH4OAc buffert/acetonitrile, 9:1 to 3:7) to give 15 mg (5% yield) of the title compound as a red solid: 1H NMR (DMSO-d6, 400 MHz) δ 14.88 (br s, 1 H), 11.03 (br s, 1 H), 9.10 (br s, 1 H), 8.28 (d, J=6 Hz, 1 H), 8.04-7.96 (m, 1 H), 7.95-7.83 (m, 1 H), 7.42-7.34 (m, 1 H), 7.13-7.02 (m, 2 H), 3.62-3.50 (m, 2 H), 2.86-2.69 (m,.2 H), 2.58-2.29 (m, 6 H); MS (TSP) m/z 350 (M++1).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH:12]([CH3:14])[CH3:13]>CN(C)C=O>[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[N:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=1
Reactant: O=Cc1cc(I)c[nH]1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)cc1C=O
Temperature: 25 °C
Yield: 43.2 %

Procedure:
Sodium hydride (860 mg, 55% in mineral oil, 19.7 mmol) was added to a solution of 4-iodo-pyrrole-2-carbaldehyde (3.0 g, 13.2 mmol) in dry dimethylformamide at ambient temperature under a nitrogen atmosphere. After stirring for 15 min 2-bromopropane (3.87 mL, 40.9 mmol) was added and the reaction mixture heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature, quenched with water and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue. Purification by column chromatography over silica gel (60-120 mesh) using 2% ethyl acetate in petroleum ether afforded 4-iodo-1-isopropyl-pyrrole-2-carbaldehyde (1.5 g, 43%) as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Reactant: O=C1CCCC(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4-6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hünig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][CH:6]=1.[NH3:17]>CO>[F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][CH:6]=1
Reactant: N
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cc1
Solvent: CO
Product: NC(=O)c1ccc(OCC(F)(F)F)cc1

Procedure:
A solution of methyl 4-(2,2,2-trifluoroethoxy)-benzoate (3 g., 0.013 mole) in methanol (25 ml.) is cooled using a dry-ice acetone bath, and the solution is saturated with anhydrous ammonia, then heated in a pressure reactor at 110° for 10 hours. The methanolic solution is filtered and the filtrate is evaporated. The residue is chromatographed on neutral alumina and the early fractions which elute rapidly with ethyl acetate are discarded, methyl ethyl ketone fractions are discarded and methanol fractions finally give a tan solid when evaporated. When recrystallized from ethanol the white solid is found to be 4-(2,2,2-trifluoroethoxy)benzamide, m.p. 177°-178° C.
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:10][O:11][CH:12]([O:19][CH3:20])[CH2:13][CH:14](OC)OC.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][CH:14]([CH2:13][CH:12]([O:19][CH3:20])[O:11][CH3:10])[O:4][CH2:3]1
Reactant: O=[N+]([O-])C(Br)(CO)CO
Reactant: COC(CC(OC)OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: COC(CC1OCC(Br)([N+](=O)[O-])CO1)OC
Temperature: 25 °C

Procedure:
2-Bromo-2-nitro-1,3-propanediol (0.02 m) and malonaldehyde bis (dimethyl acetal) (3.3 ml, 0.02 m) were heated, under nitrogen, in an oil bath at 96° C. Toluene sulfonic acid monohydrate (50 mg) was added after the solid melted. The reaction flask was sealed with a rubber septum and returned to the bath. Every 10 minutes the flask was flushed for one minute with a vigorous nitrogen stream to remove methanol. After 2 hours the brown viscous oil was cooled and subsequently solidified. The dark oily solid was treated with 20 ml of boiling hexane. The hot light yellow hexane solution was decanted from an insoluble black tar. Upon cooling to room temperature a slightly yellow solid crystallized out. The solid was collected and washed with hexane to give 5-bromo-5-nitro-2-(2',2'-dimethoxyethyl)-1,3-dioxane (3.5 g) m.p. 95°-97° C. A sample recrystallized from methanol melted at 96°-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[CH:14]([CH3:19])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[CH3:19][CH:14]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[O:20]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of 4-amino-6-(2,3-dimethylpentanamido)quinazoline (6.75 g) and dimethyl methoxymethylene-propanedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour and cooled to ambient temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (6.58 g). A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized from ethyl acetate to give analytically pure dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (0.45 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[NH:15][CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:28](=[O:30])[CH3:29])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1cncc(-c2cnc3c(c2)CCCN3)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(-c3cncc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
6-(5-Trifluoromethyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (200 mg, 0.72 mmol), whose synthesis is described in Step 1 of Example 4, is dissolved in DCM (25 mL). Triethylamine (220 mg, 2.1 mmol) is added followed by the addition of acetyl chloride (67 mg, 0.86 mmol) under N2 atmosphere at 0° C. The mixture is stirred at room temperature for 3 hrs. The solvent is removed and the residue is purified by preparative TLC to give 43 mg of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Reaction time: 2 h

Procedure:
In a 250 ml 3-neck round bottom flask with mechanical stirrer, septum and drying tube was added 3,4-difluoronitrobenzene (1) (12.91 g, 81.1 mmol), methanol (60 ml) and morpholine (15.93 g, 16 ml, 183 mmol). The clear solution was heated at reflux with stirring for 2 hours. The reaction mixture containing yellow crystals was cooled in an ice bath for 1 hour with stirring. The crystals were collected by filtration and dried in vacuo (1 mm) at room temperature for 3 hours (16.99 g, 93%). Homogenous by TLC (silica gel, CHCl3) Rf=0.54 (yellow spot) 1H NMR (500 MHz, CDCl3) δ 8.00 (ddd, 1H, J=9 Hz, J=2.6 Hz, J=1 Hz), 7.92 (dd, 1H, J=13.1 Hz, J=2.5 Hz,), 6.92 (dd, 1H, J=8.8 Hz, J=8.8 Hz), 3.86 (dd, 4H, J=4.7 Hz, J=4.7 Hz), 3.28 (dd, 4H, J=4.7 Hz, J=4.7 Hz). LCMS (Method A) 0.79 min m/e 227.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[CH2:23](O)[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Reactant: CCCC/C=C\CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1ccc(-c2ccc(CCCCCOCCC)cc2)nc1
Yield: 59.6 %

Procedure:
1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyridine, 0.42 g of (Z)-3-octen-1-ol, 0.58 g of diethyl azodicarboxylate, 0.88 g of triphenylphosphine and 100 ml of tetrahydrofuran are reacted in an analogous manner to Example 3 to give 0.8 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenyl]oxy)pyridine.
Reaction SMILES: C[N:2]1[CH2:11][CH2:10][C@@:9]2(C3C=CC=C(OC)C=3)[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:3]1[C@H:4]2[C@@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][NH:2]1
Reactant: COc1cccc([C@@]23CCCC[C@H]2CN(C)CC3)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: C1CC[C@H]2CNCC[C@@H]2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 800 mg of N-methyl-4a-(m-methoxyphenyl)-trans-decahydroisoquinoline (3.09 mmoles) in 30 ml of methylene chloride was added in portions to an ice-cold solution of 0.59 ml (1.55 g, 6.18 mmoles) of boron tribromide in 15 ml of methylene chloride. The solution, protected under nitrogen, was kept overnight at 25° C. Methanol (5 ml) was then added and the solution evaporated. The residue was treated with 15 ml of 5 N aqueous sodium hydroxide and the mixture stirred for 15 minutes. Ether (50 ml) was added and the bilayer mixture stirred for 2 hours. The aqueous and ether layers were finally separated and the aqueous portion saturated with carbon dioxide. The resulting solid precipitate was extracted with ether and the extract concentrated to give 680 mg of N-methyl-4a-(m-hydroxyphenyl)-trans-decahydroisoquinoline, mp 195°-205° C.