Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:35])([F:34])[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]3[CH:27]=[C:28](O)[CH:29]=[CH:30][C:31]=3[CH2:32][C@H:21]12)=[O:19].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[F:35][C:17]([F:16])([F:34])[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]3[CH:27]=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:29]=[CH:30][C:31]=3[CH2:32][C@H:21]12)=[O:19]
Reactant: O=C(N1CCC[C@@H]2c3cc(O)ccc3C[C@@H]21)C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (5.6 mL) is added dropwise to a solution of 2,2,2-trifluoro-1-(cis-6-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (7.3 g), triethylamine (7.2 mL), and 4-dimethylaminopyridine (50 mg) in dichloromethane (60 mL) chilled in an ice bath. The solution is stirred with cooling for 1 h and at room temperature for 2 h. Water (100 mL) and dichloromethane (100 mL) are then added and the organic phase is separated. The organic phase is washed with water (50 mL), dried (MgSO4), and concentrated to give the title compound as a dark oil. Yield: 10.7 g (quantitative); TLC: rf=0.50 (silica gel, cyclohexane/ethyl acetate 3:1); Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)[CH2:2][CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Pt]>[C:16]([O:13][N:8]1[C:7]([CH3:14])([CH3:15])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:10][C:9]1([CH3:12])[CH3:11])(=[O:18])[CH3:17]
Reactant: CCCOC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Reactant: CC(=O)OC(C)=O
Agent: [Pt]
Product: CCCOC1CC(C)(C)N(OC(C)=O)C(C)(C)C1

Procedure:
A mixture of 21.4 g (0.1 mol) of 4-propoxy-2,2,6,6-tetramethylpiperidine N-oxide (for preparation, see DE-A-4 219 459) and 11 g (0.108 mol) of acetic anhydride is hydrogenated to saturation at 4 bar over 0.15 g of platinum (10% on carbon). The catalyst is filtered off and the filtrate is diluted with 50 ml of t-butyl methyl ether, washed with cold 12% NaOH solution, 5% HCl and finally water, dried over MgSO4 and freed of the solvent on a rotary evaporator. This gives 18.1 g (70%) of the compound 112 which is in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21](=[O:27])OC(C)(C)C)[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=C=O.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21]([NH:28][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:27])[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccnc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cccnc1)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.33 h

Procedure:
(Step 2-i) tert-Butyl (R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethylcarbamate (50 mg, 0.13 mmol) was dissolved in 5 mL TFA:CH2Cl2 (1:1) and left standing for 20 min. The solvent was removed under reduced pressure and CH2Cl2 was added and removed 4 times to remove residual TFA. The amine was dissolved in 1 mL NMP and 3-isocyanatopyridine (20 mg, 0.17 mmol) was added followed by the addition of DIEA (0.086 mL, 0.5 mmol). The reaction mixture was microirradiated at 100° C. for 10 min, loaded onto a preparative reversed-phase HPLC column, and the column eluted with a H2O/CH3CN 0.1% TFA gradient. Fractions containing pure product were combined and concentrated, 6M HCl was added, and the resulting solution concentrated to give the product, 1-((R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-3-(pyridin-3-yl)urea, as the HCl salt (31 mg, 0.076 mmol, 58% yield): 1H NMR (500 MHz, DMSO-d6) 10.30 (s, 1H), 10.00 (s, 1H), 9.10 (d, J=2.2 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.31 (dd, J=1.2, 8.7 Hz, 1H), 8.16 (d, J=9.8 Hz, 1H), 7.94-7.89 (m, 2H), 7.76 (dd, J=1.5, 8.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 7.06 (dd, J=1.4, 8.0 Hz, 1H), 5.52 (t, J=7.3 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H); MH+409.20.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH2:40][CH3:41])[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:45]=[CH:46][CH:47]=[CH:48][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH2:40][CH3:41])[CH:33]=3)[C:42](=[O:43])[N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:45]=[CH:46][CH:47]=[CH:48][C:16]=2[NH:15]1
Reactant: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 2 h

Procedure:
30 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added at RT to a solution of 80 mg (0.16 mmol) (R)-1-carboxy-2-(3-ethyl-4-hydroxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 57 mg (0.18 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 2 h. The reaction solution was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH3:11])[CH:3]=2)=[CH:19][CH:18]=1)#[N:27]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: Cc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: Cc1cc(NCc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
3.35 g (20 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620) and 4.17 g (20 mmol) 4-aminomethyl-2'-cyanobiphenyl were heated with reflux in 40 ml dry ethanol for 4 hours. The solvent was distilled off in vacuo, and the remaining oil solidified after stirring with a mixture of 20 ml hexane and 20 ml t-butylmethylether to give a reddish powder of the pure title compound,
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[ClH:1].[ClH:1].[CH3:29][N:19]([CH3:18])[CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:27][CH2:28]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Product: CN(C)CCCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)nn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (3-dimethylaminoprop-1-yl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.N#N>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Yield: 69.8 %

Procedure:
A flask-containing a solution of 2-{4-[1-(4-chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 41, 30 mg, 0.08 mmol) in 1:1 ethanol/ethyl acetate (6.0 mL) was charged with N2 and evacuated (3×). Palladium on carbon (10 wt %) was added to the solution, and the flask was charged with H2 and evacuated (3×), and then maintained at ˜1 atm H2 for 2.5 h. The flask was evacuated and then charged with N2. The reaction mixture was filtered through a pad of Celite®, which was washed with ethanol (50 mL), ethyl acetate (50 mL) and then methanol (2×50 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded the title compound (21 mg, 68%). TLC (silica, 1% methanol saturated with ammonia/9/% methanol/CH2Cl2): Rf=0.35. MS (ESI+): mass calculated for C22H18ClN3O, 375.1, m/z found, 376.1. [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.16 (br s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.62 (br s, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.30-7.26 (m, 4H), 4.27-4.24 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[CH:25]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
To a solution of 5-ethoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.22 g, 0.708 mmol) in DMSO (4 mL) was added phenyl pyridin-3-ylcarbamate (0.151 g, 0.708 mmol) followed by triethylamine (0.265 mL, 2.12 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (38% acetone, 62% hexane) to give the title compound (0.17 g, 55%). 1H NMR (500 MHz, CDCl3): δ 8.44 (d, J=1.8 Hz, 1H), 8.25 (d, J=4 Hz, 1H), 8.0 (s, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.23 (m, 3H), 6.97 (d, J=4.05 Hz, 3H), 692 (d, J=4 Hz, 2H), 6.86 (d, J=8.8, 1H), 6.38 (s, 1H), 4.03 (t, J=6.95, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.56 (t, J=5.7 Hz 2H), 2.43 (t, J=5.1 Hz, 2H), 1.40 (t, J=8.25 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 157.32, 155.27, 154.5, 151.85, 143.96, 141.15, 128.78, 137.64, 136.16, 133.59, 129.42, 127.40, 126.82, 124.83, 124.57, 123.58, 120.54, 118.31, 112.54, 64.62, 53.43, 45.71, 44.71, 41.01, 35.73, 29.14, 14.82; m/z (431.2, M+ H+); HPLC: 98.8%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:46])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:46])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown solid (510 mg, 86%).
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.O[O:22][S:23]([O-:25])=O.[K+].[OH-].[Na+]>CO.O>[O:22]=[S:23]1(=[O:25])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: COC(=O)c1ccc(C2=CCSc3ccccc32)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C2=CCS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 4-(2H-1-benzothiopyran-4-yl)benzoate from reaction 33b (0.77 g, 2.75 mmol) was dissolved in methanol (30 mL) cooled to 0° C. and Oxone® (6.76 g, 11.1 mmol) in water (7 mL) was added. The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature and stir for another hour. The reaction was diluted with water, pH adjusted to pH=8 with 1 N sodium hydroxide. This was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated to give methyl 4-(1,1-dioxido-2H-1-benzothiopyran-4-yl)benzoate (0.784 g, 91%) as a solid.
Reaction SMILES: [C:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5])#[N:2].[OH-].[Na+:11]>O>[Na+:11].[C:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([O-:6])=[O:5])#[N:2]
Reactant: CCCC(C#N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C#N)C(=O)[O-]

Procedure:
An initiator solution of cyanovaleric acid sodium salt was prepared in a round bottomed flask under nitrogen by taking cyanovaleric acid (6.2 g), sodium hydroxide aq solution (33.2 ml, 1moldm-3) and water (84cm3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[CH3:17])([O-:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:18](=[O:20])[CH3:19])[CH:8]2[CH3:17])([O-:3])=[O:2]
Reactant: CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1C
Yield: 83 %

Procedure:
22.9 g (0.1 mole) of 1-nitro-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline is boiled with 120 ml of acetic anhydride for 1 hour, then the solution obtained is poured into water. The product that solidifies is filtered off, washed with water and dried. Thus, 25.0 g (83%) of 1-nitro-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 149°-150° C.
Reaction SMILES: F[C:2](F)=[C:3](F)F.[K].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.O>CN(C)C=O>[C:13]1([O:14][C:8]2[CH:13]=[CH:12][C:2]([CH3:3])=[CH:10][CH:9]=2)[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1
Reactant: FC(F)=C(F)F
Reactant: Cc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Tetrafluoroethylene pentamer (50 g) was added dropwise to the potassium salt of p-cresol (15 g) stirred in dry dimethyl formamide (100 ml) at 30° C. After addition of the pentamer, the reaction mixture was stirred for 45 minutes at 60° C. The cooled reaction mixture was poured into water. The oil which separated out was dissolved in ether, the ether layer washed with water, dried over magnesium sulphate, and distilled to give 40 g of the p-cresyl ether, C10F19OC6H4CH3, boiling point 110° C. to 114° C. at 10 mm Hg. Elementary analysis, infra-red spectra, mass spectrometry and nuclear magnetic resonance measurements confirmed the identity of the compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=1.[C:17]([OH:21])(=[O:20])[CH:18]=O>>[OH:12][C:10]1([CH3:11])[O:21][C:17](=[O:20])[CH:18]=[C:9]1[C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=[CH:5][C:6]=1[O:13][CH3:14]
Reactant: COc1ccc(C(F)(F)F)cc1CC(C)=O
Reactant: O=CC(=O)O
Product: COc1ccc(C(F)(F)F)cc1C1=CC(=O)OC1(C)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
5-(Trifluoromethyl)-2-methoxyphenylacetone (2800 mg, 12 mmol) was mixed with glyoxylic acid (2.7 mL 18 mmol) and stirred at 100° C. for 16 hours. The reaction mixture was then concentrated in vacuo and azeotroped with toluene to afford the title compound (3.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)[CH3:12].C(O)C>ClCCl>[CH2:11]([O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1)=[O:10])[CH3:12]
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromopyridine-5-carboxylic acid (J.Org.Chem., 12, 456 (1947)) (2.32 g, 11.49 mmol) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (3.12 g, 12.64 mmol) in dichloromethane (30 ml) was stired at room temperature for 1 hour under nitrogen. Absolute ethanol (5 ml) was added and the mixture stirred for 30 minutes and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (40 ml) and 10% w/w aqueous potassium carbonate solution (40 ml). The aqueous layer was extracted with dichloromethane (25 ml) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel, eluting with dichloromethane gave 2-bromopyridine-5-carboxylic acid ethyl ester (2.18 g, 83%) as a colourless oil.
Reaction SMILES: C(NN)(=O)C1C=CC=CC=1.[C:11]1([CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:11]1([CH2:17][C:18]([NH:20][NH:21][C:34]([C:33]2[CH:37]=[CH:38][N:39]=[C:31]([NH:30][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:32]=2)=[O:35])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NNC(=O)Cc1ccccc1
Agent: NNC(=O)c1ccccc1
Product: O=C(Cc1ccccc1)NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 65 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace benzohydrazide with 2-phenylacetohydrazide to react with 2-benzamidoisonicotinic acid, N-(4-(2-(2-phenylacetyl)hydrazinecarbonyl)pyridin-2-yl)benzamide was obtained in 65% yield: MS (ES+) m/z 374.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[F:20][C:14]1[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:29]4[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][S:3][C:2]([NH2:1])=[N:22]3)[C:18]=2[CH:17]=[C:16]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH:15]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3cccnc3)cc12

Procedure:
The titled compound was synthesized by stpes analogous to those described in method AA8 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 3-pyridineboronic acid pinacol ester. MS m/z=459.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:22]=3[CH3:23])=[O:17])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1
Reactant: CN(C)CCCl
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCN(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
N-[3-Cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (2 g), 2-dimethylaminoethyl chloride hydrochloride (0.85 g) and potassium carbonate (0.8 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 3 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.3 g), melting point: 185° C.
Reaction SMILES: [C:1]([O:4][C@@H](COS(C1C=CC(C)=CC=1)(=O)=O)CC#N)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:24])[CH3:23].Cl.[CH2:26]([OH:28])[CH3:27]>>[OH:28][CH:26]([CH2:2][C:1](=[O:3])[O-:4])[CH2:27][N+:22]([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(=O)O[C@H](CC#N)COS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C
Reactant: CCO
Agent: Cl
Product: C[N+](C)(C)CC(O)CC(=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of (R)-3-acetyloxy-4-tosyloxybutanenitrile (4.07 g, 13.70 mmol) in ethanol (40 mL) was added excess aq., trimethyl amine, refluxed overnight and the solvents in the reaction mixture were evaporated. To the resulting residue was added cone. HCl and heated to 80° C. for 6 h after evaporation of the solvent the residue containing crude (R)-carnitine was purified over an on exchange column, chromatography (Amberlite IR-120 W). The column was first eluted with water until the fractions were neutral and later with 10% NH4OH. Evaporation of the basic fractions gave a thick oil, which was again acidified with cone. HCl. Evaporation of the solvent afforded carnitine as hydrochloride salt. Trituration with isopropanol afforded colourless solid of (R)-carnitine hydrochloride, m.p. 44-146° C.; [α]30D=−22.4 (c 1.5, H2O); 1HNMR (200, D2O) δ 2.60-2.70 (m, 2H), 3.24 (s, 9H); 3.48-3.55 (m, 2H); 4.60-4.75 (m, 1H); 13CNMR (75 MHz, D2O) [[n]] 39.9, 54.2, 62.8, 69.7, 173.8; Mass (FAB) 162 (M++1).