Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].O.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16][C:21]21[CH2:22][CH2:23][CH2:18][CH2:28]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C1CCCC1
Product: CN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCC2
Yield: 105.9 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (300 mg, 1.29 mmol), p-toluenesulfonic acid monohydrate (120 mg) and cyclopentan-1-one (10 mL) in toluene (30 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: DCM=1:9) to afford the title compound (200 mg, yield 52%) as an orange solid:
Reaction SMILES: [BrH:1].Cl[C:3]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1>BrCBr>[Br:1][C:3]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1
Reactant: Br
Reactant: CCOC(=O)C1CC(Cl)=NN1c1ncccc1Cl
Solvent: BrCBr
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Yield: 99 %

Procedure:
Hydrogen bromide was passed through a solution of ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. product of Step B) (8.45 g, 29.3 mmol) in dibromomethane (85 mL). After 90 minutes the gas flow was terminated, and the reaction mixture was washed with aqueous sodium bicarbonate solution (100 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (9.7 g, 99% yield), which crystallized on standing.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH2:6]([OH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCCCCC>[P:1]([O-:4])([O-:3])([O:2][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])=[O:5].[P:1]([O-:3])([O:2][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])([O:18][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:5].[P:1](=[O:2])([OH:5])([OH:4])[OH:3]
Reactant: CCCCCCCCCCCCO
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CCCCCCCCCCCCOP(=O)([O-])OCCCCCCCCCCCC
Product: CCCCCCCCCCCCOP(=O)([O-])[O-]

Procedure:
Further, the thus recovered 1110 g of phosphoric acid (lower layer (1)+lower layer (2)) contained 5.13 mol (503 g) of orthophosphoric acid and 0.01 mol (2.7 g) of monododecyl phosphate. 183 g (1.4 mol) of 75% phosphoric acid at the foods additive grade were supplemented to the recovered phosphoric acid and concentrated in the same manner as described above to obtain 606 g of 105.1% polyphosphoric acid (6.5 mol converted as orthophosphoric acid). The hue of the polyphosphoric acid showed no change at all, in the hue or the like as compared with that in the phosphoric acid used initially. Further, the polyphosphoric acid was used for the reaction in the same manner as above by dropwise addition into the n-hexane solution (243 g) of 243 g (1.3 mol) of dodecyl alcohol and hydrolysis was carried out. As the result of analysis, 1.275 mol (340.5 g) of monododecyl phosphate, 0.012 mol (5.2 g) of didodecyl phosphate and 5.21 mol (510.6 g) of orthophosphoric acid (99.0% alcohol conversion rate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:23]2[CH:24]=[CH:25][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:21][CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccc(-n3ccnc3)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.7 %

Procedure:
To a mixture of (3R)-1-t-butoxycarbonyl-3-hydroxypiperidine (4.10 g, 17.8 mmol), 4-(imidazol-1-yl)phenol (4.4 g, 1.5 eq.), triphenylphosphine (1.5 eq., 7.10 g), DMF (80 mL) was added DEAD (1.5 eq., 4.33 mL). The resulting reaction mixture were stirred at room temperature for two days. The solvent was evaporated, the residue was diluted with ethyl acetate, washed with 1N NaOH (45 mL×3), water and brine, and evaporated in vacuo. Purification by flash column chromatography on silical gel with gradient 1-3% methanol in CH2Cl2 gave (3R)-1-t-butoxycarbonyl-3-[4-(imidazol-1-yl)phenoxy]piperidine (420 mg, 1.19 mmol), which was treated with trifluoroacetic acid/CH2Cl2 (1:1) from 0° C. to ambient temperature for 2 hours. The solvents were evaporated. The residue was diluted with CH2Cl2, and washed with 1N HCl (10 mL). The aqueous phase was extracted with CH2Cl2 to remove by-product. The aqueous phase was re-adjusted to pH 9.5 to 10.0 with 1N NaOH. Extraction with CH2Cl2 (60 mL×3) and evaporation of the solvent in vacuo gave (3R)-3-[4-(imidazol-1-yl)phenoxy]piperidine (62 mg) as an oil.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:3])[CH3:2].C(N1C2C=CC=CC=2SC1C1C=CC=CC=1OCC(O)C[Cl:46])(=O)C.[C:48]([NH2:52])([CH3:51])([CH3:50])[CH3:49]>C(O)C>[ClH:46].[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:52][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCC1CO1
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCC(O)CCl
Solvent: CCO
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCC(O)CNC(C)(C)C
Product: Cl
Yield: 80 %

Procedure:
1.64 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline, 1.82 g of 3-acetyl-2-[2-(3-chloro-2-hydroxypropoxy)phenyl]benzothiazoline and 10 ml of t-butylamine are dissolved in 30 ml of ethanol and the solution is refluxed for 3 hours. The solution is concentrated in vacuo, and the residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. To this solution 2N HCl/ether is added to produce crystals. Crystals are filtered to give 3.5 g (80%) of the titled compound.
Reaction SMILES: C(OC(=O)[N:7]([C:37]1[CH:38]=[N:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[C:10]([F:36])[N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH2:44]([O:43][C:40]1[N:39]=[CH:38][C:37]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([CH3:24])[CH:22]=4)[NH:17][CH:16]=3)=[C:10]([F:36])[N:9]=2)=[CH:42][CH:41]=1)[CH3:45]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To (6-ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (70, 108.1 mg, 0.166 mmol) in 4.54 mL of 1,2-dichloroethane, triethylsilane (0.454 mL, 2.84 mmol) and trifluoroacetic acid (0.27 mL, 3.5 mmol) are added and the reaction stirred at 80° C. for 4 hours. The reaction is poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 25-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3039), which is further purified by additional chromatography.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:43])[CH2:41][CH3:42])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl-:39].[Cl-:39].[Cl-:39].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:43])[CH2:41][CH3:42])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Product: [Cl-]
Yield: 261.8 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl(1-(5-((6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (120 mg, 0.19 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (78 mg, 65%) as a orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.38 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (dd, J=9.5, 2.5 Hz, 1H), 7.56-7.30 (m, 2H), 7.27 (d, J=9.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.08-3.96 (m, 1H), 3.53-3.38 (m, 3H), 3.29-3.20 (m, 2H), 2.29-2.20 (m, 1H), 2.09-1.98 (m, 1H), 1.88-1.74 (m, 2H), 1.38-1.21 (m, 3H); ESI MS m/z 521 [M+H]+; HPLC 97.6% (AUC), tR=9.86 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].C(N(CC)CC)C>C(O)C>[ClH:1].[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1ncccc1[N+](=O)[O-]
Yield: 3.7 %

Procedure:
The mixture of 2-chloro-3-nitropyridine (25.8 g, 0.16 mole), β-alanine ethyl ester hydrochloride (50 g, 0.33 mole), triethylamine (49.4 g, 0.49 mole), and 300 ml of absolute ethanol was warmed at 50°-55° C. for 4 hr with mechanical stirring. The reaction mixture was evaporated and the residue was partitioned between water and methylene chloride. The water layer was separated and extracted with methylene chloride (2×). The combined methylene chloride extracts were washed with water (2×) and dried over anhydrous sodium sulfate. The filtrate was evaporated to an orange oil (39.2 g). A 2-g sample of the oil was dissolved in acetonitrile acidified with ethereal hydrogen chloride (excess), and scratched to initiate crystallization. The yellow solid was filtered off, washed with ether, and dried under high vacuum at room temperature overnight to give 1.62 g of the title compound, mp 137°-40° C. (sealed tube).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:14](N1CCCCC1)=[O:15].[O:22]1[CH2:26]C[CH2:24][CH2:23]1>>[CH3:14][O:15][CH:23]([O:22][CH3:26])[CH2:24][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]=[O:8]
Reactant: C1CCOC1
Reactant: O=CN1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Product: COC(Cc1ccccc1C=O)OC

Procedure:
The acetal compound may be converted to the desired benzaldehyde compound by first intimately mixing the acetal compound with a metal alkyl such as n-butyllithium at very low temperatures (less than -70° C.) in an atmosphere of nitrogen to obtain a metal derivative. Thereafter, a solution of N-formylpiperidine in an inert solvent such as tetrahydrofuran is added in a dropwise manner to the suspension of the metal derivative obtain a 2-(2,2-dimethoxyethyl) benzaldehyde compound. The reaction is then quenched with saturated ammonium chloride to remove the acetal alkoxy group and to obtain the desired benzaldehyde compound which then is recovered by extraction with ether followed by evaporation of the solvent.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (362.3 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (2.8 ml) at room temperature, and the mixture was stirred at 50° C. for 15 hours. After concentration under reduced pressure, 1N hydrochloric acid was added to pH 3-4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (283 mg) as yellow crystals.
Reaction SMILES: CN(C)C(=O)C.[Br:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=2)=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[Br:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]([C:19]([O:21][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:20])=[CH:17][N:18]=2)=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cnc(-c2ccc(Br)nc2)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(OCc1ccccc1)c1cnc(-c2ccc(Br)nc2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
To an N,N-dimethylacetamide solution containing 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylic acid (4.99 g) and diisopropylethylamine (4.21 mL) was added benzyl bromide (3.81 g) under ice-cooling, after stirring the mixture for 5 minutes, the temperature of the mixture was raised to room temperature and the mixture was stirred overnight. Water was added to the reaction mixture under ice-cooling, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried to obtain benzyl 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylate (6.01 g).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]1>CCCCO>[Br:1][C:2]1[C:3]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(F)c34)cn2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(N5CCC[C@@H](NC(=O)OC(C)(C)C)C5)c34)cn2)cc1
Temperature: 155 °C
Yield: 18.5 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (230 mg, 0.518 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (311 mg, 1.55 mmol) in n-BuOH (2.5 mL) was heated to 155° C. for 48 hours in a sealed tube. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 18% yield).
Reaction SMILES: Cl.[CH3:2][CH:3]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][N:19]=1)[O:16][C:10]1([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])[CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]([C:61](O)=[O:62])[CH:52]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:54]=2)=[N:47][N:46]=[N:45]1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][N:19]=1)[O:16][C:10]1([CH2:11][CH2:12][N:13]([C:61]([C:51]3[CH:52]=[C:53]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:54]=[C:49]([C:48]4[NH:47][N:46]=[N:45][N:44]=4)[CH:50]=3)=[O:62])[CH2:14][CH2:15]1)[CH2:9][C:8]2=[O:20])[CH3:2]
Reactant: CC(C)c1cc2c(cn1)OC1(CCNCC1)CC2=O
Reactant: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc2c(cn1)OC1(CCN(C(=O)c3cc(-c4ccccc4)cc(-c4nnn[nH]4)c3)CC1)CC2=O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-(1-Methylethyl)spiro[7-azachroman-2,4′-piperidin]-4-one hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate (36 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57 mg), triethylamine (73 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 5-(tetrazol-5-yl)biphenyl-3-carboxylic acid (50 mg), and stirred at 90° C. for 1 hour and 30 minutes. Water was added to the reaction liquid, the formed precipitate was taken out through filtration, washed with hexane/ethyl acetate=2/1, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.50 (1.0H, s), 8.38 (1.0H, s), 8.04 (1.0H, s), 7.87 (1.0H, s), 7.79 (2.0H, d, J=7.6 Hz), 7.54 (2H, t, J=7.6 Hz), 7.45 (1.011, t, J=7.6 Hz), 7.40 (1.0H, s), 4.40-4.22 (1.0H, m), 3.65-3.20 (3.0H, m), 3.01 (1.0H, q, J=6.8 Hz), 2.97 (2.0H, s), 2.15-2.05 (1.0H, m), 1.95-1.78 (3.0H, m), 1.18 (6.0H, d, J=6.8 Hz). MS [M+H]+=509.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>O>[Cl:24][C:11]1[N:12]=[N:13][C:8]([CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:10]=1
Reactant: COc1cc(CCc2ccc(=O)[nH]n2)cc(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCc2ccc(Cl)nn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3,4,5-Trimethoxyphenethyl)pyridazin-3(2H)-one (2.80 g; 9.65 mmol) and phosphorus oxychloride (70 ml) was heated at 100° for 1 h, cooled to room temperature and hydrolysed by careful, gradual addition to water over 3 h, so that the temperature did not exceed 30°. The mixture was then basified to pH12 by the addition of sodium hydroxide solution (10N, 700 ml) and then left at 4° overnight. The precipitate was filtered at the pump, washed well with water to remove inorganic salts and the residue on the sinter taken up in dichloromethane. After drying (sodium sulphate), removal of the solvent gave a light-brown solid (2.84 g) which was purified by `flash` chromatography on silica, with 10% of ethyl acetate/dichloromethane as the eluent. Appropriate fractions were combined to give a white solid (2.16 g), m.p. 105°-106°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl>[OH:16][C:15]1[C:14]([OH:18])=[N:11][C:3]2[C:2](=[CH:10][CH:9]=[C:5]3[N:6]=[CH:7][S:8][C:4]3=2)[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2ncsc2c1N
Agent: Cl
Solvent: O
Product: Oc1nc2ccc3ncsc3c2nc1O
Yield: 87.8 %

Procedure:
A solution of 6,7-diaminobenzothiazole (1.3 g, 7.9 mmol) and oxalic acid dihydrate (1.3 g, 10.3 mmol) in 40 ml of 4M hydrochloric acid was refluxed on an oil bath for 11/2 h, and cooled. The resulting precipitate was collected by filtration and washed successively with water and ethanol to give 1.52 g (88%) of the title compound; m.p.>360° C.; IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): ca. 6.3 (very broad s, 1H, OH), 7.40 (d, J=9 Hz, 1H, ArH), 7.87 (d, J=9 Hz, 1H, ArH), 9.33 (s, 1H, H-2), 12.07 (broad s, 1H, OH).
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)[C:7](=[O:14])[N:6]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:23]#[N:24])[CH2:18][CH2:17]1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>C(Cl)Cl>[C:23]([CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)[N:19]1[CH2:20][CH2:21][CH:16]([O:15][NH:6][C:7]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)=[O:14])[CH2:17][CH2:18]1)#[N:24]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: N#CC(c1ccc(OC(F)(F)F)cc1)N1CCC(ONC(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
Hydrazine monohydrate (0.063 ml, 1.303 mmol) was added to a solution of 2-(4-(1,3-dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (258 mg, 0.434 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 16 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), treated with 4-fluorophenyl isocyanate (0.023 ml, 0.200 mmol) and stirred at room temperature for 14 hours. The reaction mixture was concentrated in vauo and the residue was purified by column chromatography (ethyl acetate/hexane: 50/50 to 0/100) and the resulting solid was triturated with ethyl acetate/hexane to give 1-(1-(cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (110 mg, 56%) as a white solid: LCMS: 442 [M+1]+. 1H NMR (DMSO-d6) δ: 1.67 (m, 1H), 1.81 (m, 1H), 1.94 (m, 2H), 2.33 (m, 2H), 2.58 (m, 1H), 2.88 (m, 1H), 3.76 (m, 1H), 5.47 (s, 1H), 7.10 (m, 2H), 7.46-7.60 (m, 6H), 8.62 (s, 1H), 9.43 (s, 1H).