Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(N)CN.[Li]CCCC.C[O:39]B(OC)OC.OO.Cl>C1COCC1.O>[CH3:11][N:10]([CH3:12])[C:5]1[N:4]=[C:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]([OH:39])=[C:7]([O:8][CH3:9])[N:6]=1
Reactant: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: NCCN
Product: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution at −5° C. containing 500 mg (1.10 mmol) of 5-bromo-4-hexadecyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 10 mL of anhydrous THF were added 166 μL (1.10 mmol) of N,N,N,N-tretamethyl ethylenediamine followed by 1.72 mL (2.75 mmol) of 1.6 M solution of n-BuLi in hexanes. The reaction mixture was stirred at −5° C. for 20 min. Then to the mixture were added 369 μL (3.30 mmol) of trimethoxy boron and the reaction mixture was stirred at 23° C. for 1 h. Then to reaction mixture were added 2.84 mL of 30% aq. H2O2 The reaction mixture was then stirred for 30 min and poured into 100 mL of water. The mixture was neutralized with diluted aq. HCl and extracted with two 100-mL portions of ethyl acetate. The combined organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as white solid: yield 240 mg (55%); mp: 78-79° C.; silica gel TLC Rf=0.50 (4:1 hexanes-ethyl acetate); 1H-NMR (dmso-d6) δ 0.81 (t, 3H, J=6.0 Hz), 1.23-1.19 (br m, 26H), 1.52 (quint, 2H, J=6.8 Hz), 2.46 (dd, 2H, J=7.2, 7.2 Hz), 2.97 (s, 6H) and 3.82 (s, 3H); 13C NMR (dmso-d6) δ 14.38, 22.53, 27.65, 29.14, 29.27, 29.32, 29.38, 29.43, 29.46, 29.46, 29.46, 29.46, 29.46, 29.46, 31.20, 31.73, 37.27, 37.27, 53.13, 127.10, 155.54, 156.81 and 159.70.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13][C:12]3([CH3:18])[CH3:17])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNCCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(S(C)(=O)=O)CCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a cloudy solution of (+/−)-6-bromo-4-(3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 3 of Example 1 (300 mg, 0.625 mmol) and DIPEA (0.436 mL, 2.499 mmol) in dichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride (0.058 mL, 0.750 mmol) and the resulting mixture was stirred at rt for 3 h. Reaction was diluted with dichloromethane (150 mL), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the title compound as a tan solid (94% yield). HPLC (condition B): retention time=3.11 min. LCMS (condition H): m/z 444, 446 +ve.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH:11]([CH3:17])[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: CC1CCNC(=O)c2cc3cc(F)cc(Br)c3n21
Reactant: OB(O)c1ccc(F)cc1
Product: CC1CCNC(=O)c2cc3cc(F)cc(-c4ccc(F)cc4)c3n21

Procedure:
The title compound, grey solid (79 mg, 97%), MS (ISP) m/z=327.2 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from (RS)-7-bromo-9-fluoro-5-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 3) (77.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1)(=[O:3])[CH3:2].[CH3:35][I:36]>>[I-:36].[C:1]([N:4]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=1[CH3:35])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Reactant: CI
Product: CCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(C)=O)cc1C(C)(C)C
Product: [I-]
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A mixture of 1.56 g of product from Example 133 and 23.68 g of methyl iodide is heated in a sealed tube, in the dark, at 105° C. for 18 hours. The reaction is concentrated in vacuo to give 1.86 g of the desired product as light yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20]>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([NH2:15])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20]
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(N)cn2C)cc1C(=O)NCCN1CCOCC1
Reaction time: 4 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (86 mg, 0.212 mmol; see Preparation 1 (iv) above) was suspended in methanol (25 mL) to which Pd/C-10% (80 mg) was added at 0° C. under nitrogen with stirring. The reaction mixture was hydrogenated for 4 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and methanol was removed under reduced pressure to give the amine, which was dissolved in DMF (1 mL, dry). The resulting amine was utilised in the next step without purification.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=1>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:1]([C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[N:2]=[C:18]([CH:19]([CH3:21])[CH3:20])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: NNc1cnccn1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2cnccn2)n1
Yield: 62.1 %

Procedure:
The hydrazino pyrazine (20.20 g, 183 mmol, prepared as in J. Orq. Chem., 27, 3243 (1962)) was added in portions to the 1,3-diketone (34.7 g, 167 mmol, prepared in Example 1, Step A) in glacial acetic acid (400 mL). The reaction was refluxed for 2 hours, concentrated, and partitioned between EtOAc and K2CO3 (aq). The organics were dried (MgSO4) and evaporated to give a brown solid. Recrystallization from hexanes afforded 29.27 g (62%) of a cream colored solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:11][C:12]([C@@H:14]1[CH2:19][N:18]([CH:20]=[O:21])[CH2:17][CH2:16][N:15]1C(=O)C(F)(F)F)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O.C(O)C(C)C>[C:7]([NH:11][C:12]([C@@H:14]1[CH2:19][N:18]([CH:20]=[O:21])[CH2:17][CH2:16][NH:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CO
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1
Yield: 136.3 %

Procedure:
A solution of 25.5 g (184.5 mmol) of potassium carbonate in 130 ml of water was added to 15.0 g (48.5 mmol) of (S)-4-formyl-1-(trifluoroacetyl)-piperazine-2-carboxylic acid tert-butylamide in 130 ml of isobutyl alcohol and the mixture was heated at 60° to 65° C. for 1 hour. After phase separation, the aqueous phase was extracted with 100 ml of isobutyl alcohol and the combined organic phases were evaporated to give 14.10 g of the crude title compound (still containing solvent) in the form of a light yellow oil. Other data concerning the title compound was:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH3:9][O:10][S:11](=[O:15])(=O)[O:12]C>C1(C)C=CC=CC=1>[CH3:1][S:11]([O-:12])(=[O:15])=[O:10].[CH2:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH3:9])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: COS(=O)(=O)OC
Reactant: C=CCn1ccnc1
Solvent: Cc1ccccc1
Product: C=CC[n+]1ccn(C)c1
Product: CS(=O)(=O)[O-]
Yield: 210.4 %

Procedure:
To a 200 ml four necked flask equipped with a stirrer, a dropping funnel, a cooling tube and a thermometer, 54.07 g (0.5 mol) of 1-allyl imidazole and 50 ml of toluene were charged, to which 63.01 g (0.50 mol) of dimethyl sulfuric acid was dropped slowly taking one hour or more and reacted for 5 hours. After reaction, 114.79 g of 1-allyl-3-methyl imidazolium methyl sulfonate was obtained by drying under a reduced pressure. Then, 114.79 g of the obtained 1-allyl-3-methyl imidazolium methyl sulfonate was dissolved in 80 ml of water, and a solution in which 74.44 g of lithium hexafluoro phosphate was dissolved in 80 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and water washing five times, and vacuum drying was applied to obtain 127.37 g of 1-allyl-3-methyl imidazolium hexafluoro phosphate. As a result of ICP analysis, the total alkali metals was 2.1 ppm, chloride ion was 0.4 ppm, and each of iodide and bromide ions was 0.1 ppm or less (lower than ICP detection limit).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.O.[S-2:13].[Na+].[Na+].O>C(O)C>[N:3]1([CH2:2][S:13][CH2:2][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[N:4]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: ClCn1nnc2ccccc21
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)nnn2CSCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
1-(Chloromethyl)benzotriazole (20.4 g), prepared above, and sodium sulfide monohydrate (14.4 g) in anhydrous ethanol (75 ml) were stirred overnight (20 hours) at room temperature. Water (240 ml) was added to the reaction mixture. The precipitate was filtered, washed with water to remove inorganic salts and dried. Crystallization from ethanol gave 15.6 g (88%) of desired product (Compound 1); m.p. 179°-181° C. (lit. 182°-184° C.). Thin Layer Chromotography in (CHCl3 /Ethyl acetate) showed only one spot.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
2.16 g (13.1 mmol) of ethyl 4-aminobenzoate was dissolved in 20 ml of benzene. 2.97 g (13.0 mmol) of 1,5-dibromopentane and 4.53 ml (26.0 mmol) of diisopropylethylamine were added to the solution, and they were heated under reflux for 48 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[C:10]2[CH:9]=1)([CH3:4])[CH3:3].[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)C>[CH3:4][C:2]([Si:5]([CH3:37])([CH3:36])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[C:10]2[CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccn2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccnc(S(C)(=O)=O)n3)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1ccn2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccncn3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-3-[2-(methylsulfonyl)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (3.00 g, 5.56 mmol) in DCM (90 mL) and ethanol (90 mL), NaBH4 (526 mg, 13.9 mmol) was added one portion at rt. The mixture was stirred at rt for 1 h. The reaction mixture was poured into aq. 1N NaOH and extracted with DCM. The organic layer was combined, washed with brine and dried (Na2SO4). The solvent was evaporated under reduced pressure. Chromatography on silica gel eluting with DCM/EtOAc gradient (0-20% EtOAc) gave a pale yellow solid (1.87 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(Cl)=[S:10]>C1COCC1>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[O:8][C:9]=1[SH:10]
Reactant: Nc1cccnc1O
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: Sc1nc2cccnc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-pyridin-2-ol (5.51 g, 50.0 mmol, 1.0 equiv) in anhydrous THF (175 mL) was added slowly thiophosgene (6.90 g, 4.57 mL, 60.0 mmol, 1.2 equiv) via syringe pump over a time period of 1 h. After stirring for 24 h at rt, excess thiophosgene was quenched by addition of a conc. solution of ammonium chloride (100 mL) and the majority of solvent was removed by evaporation under reduced pressure. A solution of 10 N NaOH (50 mL) was added and the residue extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 yielding 5.2 g (69%) of crude product, which was used in the subsequent reaction step without further purification. 1H NMR (300 MHz, DMSO): δ 6.30 (t, J=7.0 Hz, 1H), 7.29 (dd, J=7.0 Hz, 1=1.8 Hz, 1H), 7.45 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 13.04 (br s, 1H). MS (ISP): 152.9 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([NH2:24])[CH:23]=1)[C:18]([OH:20])=[O:19].[C:25]([O-:28])(=O)[CH3:26].[K+].Cl>O1CCOCC1.O>[C:5]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([NH:24][C:7](=[O:8])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:4])[CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:4])[C:6]1[C:25](=[CH:26][CH:12]=[CH:11][CH:10]=1)[OH:28]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(NC(=O)c2ccccc2O)cc(NC(=O)c2ccccc2O)c1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of 17.5 g of 2-acetoxybenzoylchloride in 20 ml of dioxane was added at one time to a mixture of 4.6 g of 3,5-diaminobenzoic acid, 15.3 g of potassium acetate and 80 ml of water while stirring at a temperature of from 0° to 5°C. The stirring was continued at that temperature for one hour, then at room temperature for 30 minutes and at 50°C for 30 minutes. The resulting reaction mixture was added to 200 ml of cold diluted hydrochloric acid and the undissolved substance was separated. The substance was dissolved in about 100 ml of 1N NaOH aqueous solution and then the solution was treated with active carbon and acidified with hydrochloric acid so as to bring the pH of the solution to 3 - 4 thereby precipitating crystals. The crystals were recovered by filtration and washed with water. Recrystallization from methanol-water gave 7.2 g of 3,5-bis(salicylamido)-benzoic acid having a melting point between 305° - 108°308°(decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][N:9]3[C:8]=2[CH:15]=1)([O-])=O.[H][H]>[Pd].CO>[N:12]1[CH2:13][CH2:14][N:9]2[C:8]3[CH:15]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[S:11][C:10]=12
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCN=C1S2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)N1CCN=C1S2

Procedure:
A mixture of 11 parts of 2,3-dihydro-6-nitroimidazo-[2,1-b]benzothiazole and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from dimethylbenzene. The product is filtered off and dried, yielding 5.6 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine; mp. 204°-210° C.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH:7]([F:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9].C1COCC1.O>CO>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([F:23])[C:6]([OH:24])=[O:5])=[CH:16][CH:15]=1
Reactant: COC(=O)C(F)C(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(F)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
LiOH.H2O (25 mg, 0.59 mmol) was added to a solution of N-biphenyl-4-yl-2-fluoro-malonamic acid methyl ester (114 mg, 0.39 mmol) in a mixture of methanol (0.5 mL), THF (1 mL) and H2O (0.3 mL). The resulting mixture was stirred for 2 hours at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 35 mg (32%) of N-biphenyl-4-yl-2-fluoro-malonamic acid
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:7]([C:8]([O-:10])=[O:9])=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([OH:3])=[O:2]>[OH-].[Na+]>[C:1]([CH2:4][N:5]1[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:7]([C:8]([OH:10])=[O:9])=[C:6]1[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)([OH:3])=[O:2]
Reactant: Cc1cc(=O)c(C(=O)[O-])c(-c2ccc(Cl)cc2)n1CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(-c2ccc(Cl)cc2)n1CC(=O)O
Yield: 72.3 %

Procedure:
4.0 g of 1-carboxymethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate is suspended in 40 g of 5% aqueous sodium hydroxide solution and heated at 80°-85° C. for two hours. The reaction mixture is cooled and acidified to give a white precipitate. This precipitate is collected by filtration to yield 2.9 g of 1-carboxymethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinic acid. mp (CH3CN)=158°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:19]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCC(CCC)C(N)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCC(CCC)C(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.5 %

Procedure:
To a stirred solution of 1-(3′,4′-dimethoxyphenyl)-2-propylpentylamine (0.40 grams, 1.60 mmol) and sodium carbonate (0.18 grams, 1.72 mmol) in a mixture of water (5 milliliters) and acetonitrile (10 milliliters) was added N-carbethoxyphthalimide (0.35 grams, 1.60 mmol). The resulting solution was stirred for 2.5 hours at room temperature, the acetonitrile was evaporated and a two phase mixture resulted. The organic phase was extracted into methylene chloride, dried over magnesium sulfate and concentrated in vacuo to afford 0.6 grams of crude product as an oil. The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to afford 0.25 grams of the product as an oil which after a few days solidified. The white solid was dried in vacuo (60° C., <1 mm) to afford 0.24 grams of pure product as a white solid: mp 100-101° C.; 1H NMR (CDCl3) δ7.84-7.59(m, 4H), 7.27-7.02(m, 2H), 6.81-6.68(m, 1H), 5.01(d, J=12 Hz, 1H), 3.89(s, 3H), 3.84(s, 3H), 3.17-2.98(m, 1H), 1.49-0.66(m, 14H). 13C NMR (CDCl3) δ168.5, 148.7, 148.4, 133.8, 131.9, 131.8, 123.1, 121.6, 112.0, 110.7, 58.9, 55.9, 55.7, 36.2, 31.9, 31.8, 18.7, 18.1, 14.6, 14.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1.[NH3:17]>C(O)C.CO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH2:17])[CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1-n1cccn1
Reactant: N
Solvent: CCO
Solvent: CO
Product: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86 %

Procedure:
To a solution of 1-(5-bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole (240 mg, 0.84 mmol) in ethanol (3 mL) was added ammonia (3 mL, 2N in methanol. The resulting mixture was heated in a sealed tube at 80° C. for 16 hours then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:3) to afford 205 mg (86%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 5.20 (br s, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d, 1H), 7.8 (d, 1H). MS M+1 283, M+1+2 285.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[C:16]=1[CH2:22][CH3:23]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[C:16]=1[CH2:22][CH3:23])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCc1c(Br)cccc1I
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1CC
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a solution of malonic acid diethyl ester (24.72 g, 154.36 mmol) in dioxane (400 mL) was added sodium hydride (6.17 g, 60%, 154.36 mmol). The mixture was stirred for 15 minutes. Then 1-bromo-2-ethyl-3-iodo-benzene (D126) (40 g, 128.63 mmol) and cuprous bromide (22.13 g, 154.36 mmol) was added. The reaction mixture was refluxed for 10 hr, and then filtered. The filtrate was concentrated in vacuo to give the crude product, which purified by column chromatography to afford 2-(3-bromo-2-ethyl-phenyl)-malonic acid diethyl ester (D127) (20 g). δH (CDCl3-d6, 400 MHz): 1.13 (3H, t), 1.26 (6H, q), 2.88 (2H, m), 4.17 (1H, m), 4.93 (1H, s), 6.68 (1H, t), 7.41 (1H, d), 7.51 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][C:4]=1[N+:16]([O-])=O>N.O>[NH2:16][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:3]=1[O:2][CH3:1])[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Agent: N
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1N
Reaction time: 0.17 h

Procedure:
A solution of 3-(4-methoxy-3-nitrobenzoyl) propionic acid (10.5 g.) in 5N ammonia solution (150 ml.) was added in one portion to a stirred hot (90° C) solution of hydrated ferrous sulphate (90 g.) in water (210 ml.) and stirring was continued for 10 minutes more. The hot mixture was filtered through Hyflo and the filtrate was concentrated to 50 ml. volume and neutralised with acetic acid. The mixture was cooled, the precipitated solid collected and purified by crystallisation from dilute methanol toyield the amine, (5.5 g.), m.p. 136°-137° C.