Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si](CC)(CC)CC)=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.[CH:32]1([C:35]#[C:36][Si](C)(C)C)[CH2:34][CH2:33]1.C(N(CC)CC)C.[F-].[Cs+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:27]([O:26][C@@H:20]([C:7]1[C:6]([CH3:31])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:36]#[C:35][CH:32]3[CH2:34][CH2:33]3)[CH:3]=2)[C:8]=1[OH:12])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:30])[CH3:29]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O[Si](CC)(CC)CC
Reactant: C[Si](C)(C)C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C#CC3CC3)ccc2c1O
Temperature: 110 °C

Procedure:
A Smith process vial was charged (S)-ethyl 2-(6-bromo-3-methyl-1-(triethylsilyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (151 mg, 0.287 mmol), (cyclopropylethynyl)trimethylsilane (195 mg, 0.316 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), CuI (55 mg, 0.28 mmol), triethylamine (0.12 mL, 0.86 mmol), cesium fluoride (144 mg, 0.95 mmol) and flushed with nitrogen. THF (3 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(6-(cyclopropylethynyl)-1-hydroxy-3-methylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C24H27O4: 379.48. Found: 379.20.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][CH2:15][CH:16]2[CH2:19][NH:18][CH2:17]2)=[CH:7][CH:6]=1.CC#N.C1([O:34][C:35](=O)[NH:36][C:37]2[N:41]3[N:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][CH:38]=2)C=CC=CC=1>CCOC(C)=O>[N:39]1[CH:38]=[C:37]([NH:36][C:35]([N:18]2[CH2:17][CH:16]([CH2:15][CH2:14][O:13][C:12]3[CH:20]=[CH:21][CH:22]=[C:10]([O:9][C:8]4[CH:7]=[CH:6][C:5]([Cl:4])=[CH:24][CH:23]=4)[CH:11]=3)[CH2:19]2)=[O:34])[N:41]2[C:40]=1[CH:45]=[CH:44][CH:43]=[N:42]2
Reactant: Clc1ccc(Oc2cccc(OCCC3CNC3)c2)cc1
Reactant: O=C(Nc1cnc2cccnn12)Oc1ccccc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1cnc2cccnn12)N1CC(CCOc2cccc(Oc3ccc(Cl)cc3)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution consisting of 3-{2-[3-(4-chloro-phenoxy)-phenoxy]-ethyl}-azetidine formic acid salt (0.040 g, 0.13 mmol), TEA (0.018 mL, 0.13 mmol) and CH3CN (1.0 mL) was added imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (0.034 g, 0.13 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (40 mL). The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (0.035 g, 57%). MS (ESI+): calcd. for C24H22ClN5O3, 463.14. m/z found, 464.1 (M+H)+. 1H NMR (d6-DMSO): 8.55 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J=7.3 Hz, 2H), 7.29 (t, J=8.2 Hz, 1H), 7.19-7.15 (m, 1H), 7.04 (d, J=7.4 Hz, 2H), 6.75 (d, J=8.3 Hz, 1H), 6.61-6.55 (m, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.99 (t, J=6.1 Hz, 2H), 3.77-3.66 (m, 2H), 2.83-2.69 (m, 1H), 2.10-2.01 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[IH:21].II.S(=O)(=O)(O)O>CO.C(O)(=O)C>[C:1]1([C:7]2[CH:12]=[C:11]([I:21])[CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: I
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Ic1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A three neck flask was charged with 250 g of m-terphenyl (manufactured by Aldrich Co., Ltd.), 50 g of hydroiodic acid dihydrate, 75 g of iodine, 750 mL of acetic acid and 25 mL of cone, sulfuric acid, and they were reacted at 70° C. for 3 hours. After reaction, the solution was poured into 5 L of methanol and then stirred for one hour. This was separated by filtration, and crystal obtained was refined by means of column chromatography and recrystallized from acetonitrile to obtain 64 g of 5-phenyl-3-iodobiphenyl (intermediate 3) shown, below and 17 g of 3′-phenyl-4-iodobiphenyl (intermediate 4) shown below.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(I)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(I)ccc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(I)cc3n21
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (140 mg) was dissolved in 1,4-dioxane (2 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added and refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)-butyramide (85 mg) as light colourless solid.
Reaction SMILES: CC1C=CC(C)=CC=1.C[C:10]1[C:15]2C[O:17][C:18](=[O:19])[C:14]=2[C:13](O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=[C:12](C/C=C(/CCC(O)=O)\C)[C:11]=1OC.Br.[C:45]([OH:48])(=[O:47])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[C:45]([OH:48])(=[O:47])[C:11]1[CH:10]=[CH:15][C:14]([C:18]([OH:17])=[O:19])=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: [Co+2]
Agent: [Mn+2]
Agent: Br
Solvent: Cc1ccc(C)cc1
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
An example of the liquid-phase oxidation reaction is as follows. For example, using an apparatus with a commercial scale, p-xylene is subjected to liquid-phase oxidation by air (reaction temperature: 200 [° C.]; reaction pressure: 1.5 [MPaG]) in the presence of cobalt acetate, manganese acetate and hydrobromic acid in hydrous acetic acid to obtain a crude terephthalic acid slurry (the concentration of terephthalic acid: 34% by weight; the concentration of water in the hydrous acetic acid that is a dispersing medium: 11% by weight), and the resulting slurry is then introduced into crystallization vessels connected in series to subject the slurry to sequential pressure drop.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27])([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[O:27])=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: CC(C)NNC(=O)c1ccsc1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccsc1)C(C)C
Yield: 73.4 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (100 mg, 0.36 mmol), and tiophene-3-carboxylic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.152 ml, 1.09 mmol), HOBT (59 mg, 0.44 mmol), and EDCI (84 mg, 0.44 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (41 mg, 26%). MS m/e 441.30 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[O:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]2[O:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(-c2nc3ncccc3o2)cc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(-c2nc3ncccc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
In a typical run, 3-nitro-5-(oxazolo[4,5-b]pyridin-2-yl)benzoic acid (770 mg, 2.70 mmol) was suspended in 50 mL of anhydrous THF and cooled in an ice bath along with NMM (0.3 mL, 2.70 mmol). Isobutyl chloroformate (0.35 mL, 2.70 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. A solution of NaBH4 (102 mg, 2.70 mmol) in 6 mL of water was then added at 0° C. and the reaction mixture was stirred at the same temperature for 45 min. It was then concentrated and the resulting residue was diluted with 10 mL of water. The aqueous layer was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated to afford 500 mg of (3-nitro-5-oxazolo[4,5-b]pyridin-2-yl-phenyl)-methanol (68% yield, >95% pure by LC/MS).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:45][C:46]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][O:48][CH2:47]1>CN(C=O)C.C(OCC)(=O)C>[C:51]([CH2:50][C:46]1([NH:45][C:11]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH:8]3[CH2:9][CH2:10]3)=[CH:6][N:5]=2)=[O:13])[CH2:49][O:48][CH2:47]1)(=[O:52])[NH2:53]
Reactant: NC(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(Cl)c(C2CC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of 4-chloro-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48b, 200 mg, 1.01 mmol) in DMF (4.0 ml) were added TBTU (357 mg, 1.11 mmol) and DIEA (654 mg, 866 μl, 5.06 mmol) and the reaction mixture was stirred at room temperature for 20 minutes. Addition of 2-(3-aminooxetan-3-yl)acetamide (158 mg, 1.21 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and extracted with water. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica, eluting with a ethyl acetate/heptane gradient to yield the title compound (80 mg, 26%) as a yellow solid. MS (ESI, m/z): 310.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:19]#[N:20].[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)#[N:20]
Reactant: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Cl
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reaction time: 6 h
Yield: 32.2 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (92 mg, 0.299 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 6 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.[OH-].[K+].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1
Reactant: COc1cc(C)c2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
By a method similar to Preparation 3, using 5-methoxy-7-methyl-1H-indole (0.12 mole, 20.02 g), methanol (240 mL), potassium hydroxide (0.43 mole, 24.39 g) and 1-methyl-4-piperidone (0.13 mole, 14.76 g) afforded 24.72 (78%) of the title compound: Mass spectrum (ion spray): m/z=(ES+) 257 (M+1), (ES−) 255 (M−1); 1H NMR (DMSOd6): 7.32 (s, 1H), 7.06 (1H), 6.59 (1H), 6.05 (m, 1H), 3.75 (s, 3H), 3.04 (2H), 2.50 (m, 4H), 2.42 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:41].CO>Cl.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Tert-butyl 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1 CH2Cl2/methanol and 4N HCl in dioxane added. The reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated and dried in a vacuum oven to provide the title compound (0.473 g, 98.0% yield). 1H NMR (d6-DMSO) δ 12.39 (s, 1H), 8.95 (bs, 1H), 8.80 (bs, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.30 (d, 2H), 3.16-2.99 (m, 3H), 2.17 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([CH:13]=1)N.N([O-])=[O:18].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[C:11]([OH:18])[CH:13]=1
Reactant: Nc1cc(Br)ccc1C1CC1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Br)ccc1C1CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
An ice-cold solution of H2SO4 (0.23 mL, 4.31 mmol) in water (2 mL) was added to 5-bromo-2-cyclopropylaniline (300 mg, 1.42 mmol) at 0° C. The reaction was stirred for 10 min, then sodium nitrite (98 mg, 1.415 mmol) in 2 mL cold water was added dropwise. The reaction was stirred at 0° C. for 1 h and then heated at 100° C. for 1 h. Reaction was extracted with EtOAc. Combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound, which was used without further purification. LC-MS calculated for C9H9BrO 211.98, no ionization, (Rt: 1.57/4 min.).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1.Br.Br[CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][CH2:18][NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)[CH3:23]
Reactant: CCN(CC)CCCBr
Reactant: Nc1n[nH]c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To 80 ml of anhydrous N,N-dimethylformamide were added 4 g of 3-aminoindazole as prepared in accordance with the method described in C. E. Kwartler et al., J. Am. Chem. Soc., 65, 1804 (1943), 8.3 g of 3-bromopropyldiethylamine hydrobromide and 8.3 g of anhydrous potassium carbonate. The mixture was stirred for 24 hours at 80° C. and condensed under reduced pressure. To the condensed residue were added 100 ml of chloroform and 50 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 3.85 g of 3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(OC(O)C)C>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(F)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(F)c3)c2cc1OC

Procedure:
A mixture of 1.00 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.89 g of 3-fluoroaniline, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred at reflux temperature for 4 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate to give a solid, mp 226-230° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([CH:9]=[CH2:10])=[CH:7][N:6]=[C:5]([CH3:11])[CH:4]=1.[CH2:14]([C:16]1[CH:24]=[CH:23][C:22]2[NH:21][C:20]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:19]=3[C:18]=2[CH:17]=1)[CH3:15].[OH-].[K+]>CN1C(=O)CCC1>[CH2:14]([C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH2:10][CH2:9][C:8]3[CH:7]=[N:6][C:5]([CH3:11])=[CH:4][C:3]=3[C:2]([F:1])([F:12])[F:13])[C:20]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:19]=3[C:18]=2[CH:17]=1)[CH3:15]
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)cc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 8-ethyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: F[C:2]1[C:21](F)=[CH:20][C:5]2[N:6]=[C:7](SCC3C(C)=C(OC)C=CN=3)[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.O>[N:6]1[C:5]2[CH:20]=[CH:21][CH:2]=[CH:3][C:4]=2[NH:8][CH:7]=1
Reactant: COc1ccnc(CSc2nc3cc(F)c(F)cc3[nH]2)c1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: c1ccc2[nH]cnc2c1
Reaction time: 0.08 h

Procedure:
A solution of 13.7 g of 5,6-difluoro-2-[[(4-methoxy 3-methyl-2-pyridyl)methyl]thio]benzimidazole in 800 ml of methylene chloride and 130 ml of methanol was treated with 6.9 g of potassium carbonate. 9.6 g of m-chloroperbenzoic acid were added thereto at -30°, whereupon the solution was stirred for a further 5 minutes and subsequently poured into a mixture of 200 ml of saturated sodium bicarbonate solution and 200 ml of water. The separated organic phase was dried over sodium sulfate, treated with 5.0 ml of triethylamine and evaporated in a vacuum. Crystallization from methylene chloride-methanol-ether yielded 5,6-difluoro-2-[[(4-methoxy-3-methyl-2-pyridyl))methyl]sulfinyl]benzimidazole of melting point 188°-189°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]2=[O:22])[S:5][C:6]=1[C:7](O)=[O:8].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C)C=O>[CH2:53]([NH:60][C:7]([C:6]1[S:5][C:4]([N:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]2=[O:22])=[N:3][C:2]=1[CH3:1])=[O:8])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid (0.20 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.23 g, 1.67 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.15 g, 0.77 mmol), N,N-diisopropylethylamine (0.11 g, 0.83 mmol), and benzylamine (0.084 mL, 0.77 mmol). The reaction mixture was stirred at ambient temperature for 5 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (0.12 g, 47%): mp 235-237° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.8 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 7.87-7.77 (m, 2H), 7.52-7.49 (m, 3H), 7.34-7.18 (m, 5H), 7.08-7.00 (m, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 160.4, 153.7, 151.4, 150.6, 139.9, 135.9, 131.6, 130.9, 129.7, 128.8, 127.8, 127.5, 127.3, 124.5, 43.2, 17.6; MS (ES+) m/z 402.5 (M+1).