Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[N+:20]([O-])([OH:22])=[O:21].O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([C:15]([N+:20]([O-:22])=[O:21])=[CH:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc2ncc([N+](=O)[O-])n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (3.07 g, 6.10 mmol, prepared according to Example 3, Step 2.3) in concentrated H2SO4 (55 mL) was added a freshly prepared mixture of fuming HNO3 in H2SO4 (1:2, v/v, 2.55 mL) at RT. The reaction mixture was stirred at RT for 2 h then cautiously added to cold water (300 mL) and extracted with DCM (5×). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to dryness to give the crude 6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile as a brown solid (533 mg). MS: 333 [M+1]+; HPLC: AtRet=1.57.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>C(#N)C>[O:15]=[C:11]1[C:12]2[C:8](=[CH:7][C:6]([N:5]([CH2:32][C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:24])[N:10]1[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: ClCc1cccs1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(Cc3cccs3)S(C)(=O)=O)cc2C1=O
Temperature: 120 °C
Yield: 94.4 %

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (500 mg, 1.411 mmol) (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) in acetonitrile (10 ml), K2CO3 (390 mg, 2.82 mmol) and 2-(chloromethyl)thiophene (281 mg, 2.116 mmol) (obtainable as described in U.S. Pat. No. 5,716,943, which is incorporated herein by reference in its entirety) were added, and the reaction was heated under microwave irradiation at 120° C. for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness. The resulting crude was purified by flash chromatography on silica gel (hexane/EtOAc 2/1) affording tert-butyl 2-(1,3-dioxo-5-(N-(thiophen-2-ylmethyl)methylsulfonamido)-isoindolin-2-yl)acetate (600 mg, 1.332 mmol, 94% yield, MS/ESI+ 472.9 [MNa]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C[N:25](C=O)C>>[Br:8][C:5]1[N:4]=[C:3]2[N:9]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:25]=[N:1][C:2]2=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2nc(Br)cnc2N)C1
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Cn2nnc3ncc(Br)nc32)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
tert-butyl 3-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)piperidine-1-carboxylate (2.19 g, 5.70 mmol) was dissolved in DMF (15 ml), and isoamylnitrile (0.92 ml, 6.84 mmol) was slowly dropped at 0° C. After that, the mixture was stirred at 70° C. for 1 hour. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:8), to give tert-butyl 3-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (1.39 g, 62%).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[CH:8][CH:7]=1>CS(C)=O.CN(C=O)C>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=2)=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: [C-]#N
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (0.75 g) was added to a solution of the crude product from step (vi) in DMSO (10 ml) and DMF (10 ml). The mixture was stirred at rt for 18 h, then partitioned between EtOAc/water. The organics were separated, washed with aq NaHCO3 solution, dried and evaporated under reduced pressure to afford the subtitle compound, 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]2=[N:6][C:7]=1[I:8].C(N(CC)CC)C.Cl[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine (for preparation see WO 2012116145; 1.5 g) and triethylamine (875 μL) are dissolved in tetrahydrofurane (12 mL), cooled to 0° C. and treated with (2-(chloromethoxy)ethyl)trimethylsilane (SEM-Cl; 890 μL). The mixture is stirred for 30 minutes while warming to room temperature. Then the mixture is partitioned between saturated aqueous NH4Cl and ethylacetate. The organic phase is washed with water and brine. After drying (MgSO4) the solvents are evaporated in vacuo to give the title compound. LC (method 1): tR=1.22 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([C:7]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCOC(=O)C(O)(C=Cc1ccccc1)c1ccccc1

Procedure:
Ethyl α-phenyl-α-phenylethynylglycolate (5.6 g., 0.02 mole) in 50 ml. of absolute ethanol, 0.2 g. of palladium on barium sulfate and a drop of quinoline were placed in a Parr shaker under 40 psi of hydrogen at room temperature. The required amount of hydrogen was taken up in 13 minutes. The catalyst was filtered and the filtrate stripped of ethanol in vacuo to yield 5.7 g. (100%) of crude product. Both n.m.r. and infrared spectroscopy confirmed the structure. The material was distilled to yield 4.1 g. of liquid, b.p. 130°-43° (0.16 mm.). N.m.r. analysis of the distilled material indicated that about 5 mole % of the fully saturated derivative was present as an impurity.
Reaction SMILES: [C:1]1([CH:7]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:8][C:9]2[CH:42]=[CH:41][C:12]([CH2:13][N:14](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.SCC(O)=O.O.[OH-].[Li+].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]1([CH:7]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:8][C:9]2[CH:42]=[CH:41][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1ccc(N(Cc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(NCc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of ethyl 3-(4-{[4-(diphenylmethoxy)-3-isobutylbenzyl][(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (0.80 g, 1.10 mmol) and mercaptoacetic acid (0.17 mL, 2.45 mmol) in N,N-dimethylformamide (15 mL) was added lithium hydroxide monohydrate (0.20 g, 4.77 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=3/97-15/85) to give the title compound (552 mg, yield 93%) as a pale-yellow oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:22])[CH:5]=1>O.C(O)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:22])[CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cc(F)c(N)cc1F
Temperature: 90 °C
Yield: 40.1 %

Procedure:
Sodium hydroxide (903 mg, 22.58 mmol) in water (7 ml) was added to a solution of diethyl (4-amino-2,5-difluorophenyl)propanedioate (4.32 g, 15.05 mmol) in ethanol (35 ml). The reaction mixture was heated to 90° C. under argon for 1 hr. The reaction mixture was allowed to cool and then the solvent was evaporated. The residue was acidified (2M HCl, 200 ml) and then extracted with ethyl acetate (200 ml). The organic layer was dried (Mg SO4) and the solvent evaporated. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0→25% ethyl acetate/hexane) to afford the title compound as a pale yellow oil (1.3 g). MS (ES+) m/z 216 [M+H+] (C10H11FNO2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([O-])[O-].[K+].[K+].CI>>[CH3:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccc(C)c([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
In the manner of Example 8, Step C, the reaction of 25.0 g (0.162 mole) of 4-methyl-3-nitrophenol, 23.3 g (0.168 mole) of potassium carbonate, and 34.1 9 (0.24 mole) of methyl iodide produced 26.4 g of 1-methoxy-4-methyl-3-nitrobenzene as an oil.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:16][CH3:17])[C:13]([OH:15])=O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:34][NH:35][O:36][CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:3]1[N:2]([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:16][CH3:17])[C:13]([N:35]([O:36][CH3:37])[CH3:34])=[O:15])=[CH:10][CH:11]=2)[N:1]=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: COC(C(=O)O)c1ccc(-n2nccn2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
To a solution of 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-methoxyacetic acid (1.19 g, 5.1 mmol in anhydr CH2Cl2 (15 ml) was added 4-methylmorpholine (1.55 g, 15.3 mmol) and it was cooled over an ice bath. Isobutylchloroformate (0.84 g, 6.12 mmol) was added and stirred for 45 min. N,O-Dimethylhydroxylamine HCl (0.746 g, 7.65 mmol) was added and the mixture was allowed to stir overnight while warming to room temp. Saturated aqueous NaHCO3 (15 ml) was added and stirred for 5 min. The organic layer was dried over Na2SO4 and evaporated to dryness. Purification by chromatography (100% EtOAc) gave 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide as a white solid (0.63 g, 44% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>COC(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:18][CH:17]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)CC1CC2
Agent: [Pd]
Agent: COC(C)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)C2
Yield: 91.4 %

Procedure:
3-[4-(4-Methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (0.83 g, 1.85 mmol) is solubilized in 93 ml of methoxyethanol. Palladium-on-carbon at 10% (0.395 g) is then added. The reaction medium is stirred for 5 h under 30 psi of hydrogen at 25° C. After filtration on Celite® and concentration, 0.76 g of expected 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: C1(=O)CCCC1.O[C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[C:13]1([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1(c2ccccc2)CCCC1
Solvent: O=C1CCCC1
Product: C1=C(c2ccccc2)CCC1
Yield: 90 %

Procedure:
The same experiment as in Example 2 was carried out, except for using 2.5 g (0.03 mol) cyclopentanone instead of 1.74 g of acetone. The resulting reaction mixture was analyzed by gas chromatography to confirm that the target 1-hydroxy-1-phenylcyclopentane and phenylcyclopentene were obtained in a yield of 90% in total.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) (157 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/dichloromethane) as a light brown solid (130 mg, 52%). MS (EI) 498.1 [(M)+]; mp 294° C.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([NH:27][NH2:28])(=[O:26])[CH3:25]>C(Cl)(Cl)Cl.CO>[C:24]([N:27]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH:14]=[N:28]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NN
Reactant: O=CC=Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)N1N=CCC1c1ccccc1
Temperature: 220 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To 10 ml of diphenyl ether were added 1.3 g of cinnamaldehyde and 0.8 g of acetylhydrazine, followed by gradual heating to 220° C. over 30 minutes. Stirring was continued for 3 hours at that temperature. After cooling, the reaction liquid as such was subjected to silica gel chromatography (chloroform/methanol=100/1). Thus there was obtained 1.2 g of 1-acetyl-5-phenyl-2-pyrazoline in the form of light yellowish oil as the desired product. The yield was 64.8%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=2[CH:13]=1)#[N:2].C[Sn]([N:23]=[N+:24]=[N-:25])(C)C>C1(C)C=CC=CC=1>[NH:23]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[CH:13]=2)=[N:2][N:25]=[N:24]1
Reactant: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen bubbler was charged with 19.1 g (82 mmol) of 2-(2-cyanophenyl)-5-methylbenzofuran, 200 mL of toluene and 25.6 g (124 mmol) of trimethyltin azide. The suspension was heated at reflux for 20 hours, then an additional 10.0 g (48 mmol) of trimethyltin azide was added and heating at reflux was continued for another 24 hours. Additional trimethyltin azide (5.5 g,27 mmol) was added and refluxing continued for 5 hours. The reaction mixture was cooled to room temperature and solids were removed by filtration and washed with hexane and air dried. The solids were partitioned between 400 mL of 2N aqueous sodium hydroxide and 400 mL of ethyl acetate. The layers were separated and aqueous layer was acidified by the addition of 2N hydrochloric acid, then extracted with 100 mL of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and refrigerated for 48 hours. The crystals that formed were removed by filtration, washed with hexane and air dried to give 12.97 g (47 mmol,57%) of the product as fluffy, white crystals. 1H NMR (200 MHz,CDCl3): 2.38 (s,3H), 6.27 (s,1H), 7.05 (d,8 Hz,1H), 7.25 (m,2H), 7.4-7.7 (m,3H), 7.90 (d,8 Hz,1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[F:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.O1CCCOB1C1C=NC=CC=1>CN(C=O)C.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:37][C:15]1[CH:16]=[CH:17][C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]
Reactant: OB(O)c1cccnc1
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(-c5cccnc5)ccn34)c2)CC1
Temperature: 100 °C
Reaction time: 26 h

Procedure:
Under nitrogen, 7-bromo-N-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (Ex 1.1, step 1) (120 mg, 0.212 mmol), pyridine-3-ylboronic acid (33.8 mg, 0.212 mmol), triethylamine (0.030 ml, 0.212 mmol), cesium carbonate (69.1 mg, 0.212 mmol) and PdCl2(dppf).CH2Cl2 adduct (17.33 mg, 0.021 mmol) in DMF (3 ml) were heated at 85° C. overnight. A further portion of cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct (6.10 mg, 7.47 μmol) were added along with 3-(1,3,2-dioxaborinan-2-yl)pyridine (34.6 mg, 0.212 mmol) and heated continued at 85° C. for 26 hrs. A further portion of cesium carbonate (24.34 mg, 0.075 mmol) and PdCl2(dppf).CH2Cl2 adduct (6.10 mg, 7.47 μmol) and 3-(1,3,2-dioxaborinan-2-yl)pyridine (34.6 mg, 0.212 mmol) were added. The reaction was heated at 100° C. for 2 hrs. The reaction mixture was diluted with EtOAc and water and the resulting product which precipitated out was collected by filtration. Further product was contained in the organic phase, which was washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was combined with the precipitated product and purified by chromatography on silica eluting with 0-20% MeOH/DCM. The resulting solid was purified by preparative LC-MS eluting with 0.1% diethylamine 30-70% acetonitrile/water. The product fractions were partitioned between EtOAc and NaHCO3. The organic portion was separated, dried (MgSO4) and concentrated in vacuo to afford the title compound;
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:18]=[CH:17][C:9]2[NH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[N:12][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22]([NH:1][CH:2]([C:6]1[CH:18]=[CH:17][C:9]2[NH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[N:12][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(C(=O)O)c1ccc2[nH]c(C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC(C(=O)O)c1ccc2[nH]c(C(F)(F)F)nc2c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
9.2 g (27.1 mmol) of 14f are dissolved in 50 ml of water, and the pH is adjusted to 9 with 2N sodium hydroxide solution. The clear solution is cooled to 0°-5° C., and 8.1 ml (0.0569 mol) of benzyl chloroformate are added dropwise within 30 minutes, with simultaneous addition of 2N sodium hydroxide solution (pH range 8-10). After stirring at room temperature for 50 minutes, the mixture is extracted once with ether/ethyl acetate (1:1), and the aqueous phase is acidified to pH 2 with 2N HCl and is extracted with ethyl acetate. After washing with water and drying over Na2SO4, the residue is reprecipitated from ethyl acetate/petroleum ether.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.Cl.[O-:25][C:26]#[N:27].[K+]>O>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:6]=[CH:5][C:4]3[CH:3]([CH2:2][NH:1][C:26]([NH2:27])=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21

Procedure:
A mixture of 0.23 grams (0.688 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide, 0.15 mL 6M hydrochloric acid, and 0.112 grams (1.38 mmole) potassium cyanate in 25 mL water was heated under reflux for 1.5 hours. The solid precipitate was collected by filtration and dried in vacuo to provide 3-fluoro-N-(5-ureidomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide as a white solid, 0.21 gram (81%), m.p. 162-163° C., M+H=378.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].P([O-])([O-])([O-])=O>CO>[C:2]1([C:1]2[S:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: N#Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: O=C(O)C1CSC(c2ccccc2)=N1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3 days. The precipitate was removed by filtration, and MeOH was removed using rotary evaporation. To the remaining solution was added 1M HCl to adjust to pH=2 under 0° C. The resulting precipitate was filtered to yield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was used directly to next step without purification.