Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.Cl[CH2:11][C:12](=[O:14])[CH3:13]>C(O)C>[CH3:9][N:8]1[C:4]([S:3][CH2:11][C:12]([CH3:13])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: CC(=O)CCl
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(=O)CSc1nnnn1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3.12 g (0.02 mol) of 5-mercapto-1-methyltetrazole sodium salt hydrate in 60 ml of absolute ethanol was added dropwise, 2.06 g (0.2 mol) of chloroacetone. After stirring for 20 hours at room temperature, the ethanol was evaporated in vacuo. The residue was dissolved in methylene chloride and was washed with water and then brine prior to drying over Na2SO4. Evaporation of the methylene chloride solution gave 1-methyl-5-acetonylthiotetrazole that was purified by flash chromatography on silica gel to yield 0.94 g of the 5-acetonylthio-1-methyltetrazole product.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O)(C)(C)C.[C:16]([Li])(C)(C)C.CI.Cl>C1COCC1.CCCCC>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:16])[C:9]=1[NH2:8]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CI
Product: Cc1cccc(F)c1N
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A solution of 8.15 g (38.5 mmol) of N-t-butoxycarbonyl-2-fluoroaniline in 30 ml of dry THF was coled to -70° C., and 46.3 ml (93 mmol) of 2.0M t-butyllithium in pentane was added dropwise at a rate sufficient to maintain the temperature below -65° C. When the addition was complete the reaction mixture was stirred at -70° C. for 15 minutes, warmed to -20° C. and stirred for 2.5 hours. A solution of 6.8 g (30 mmol) of methyl iodide in THF was added and the reaction was allowed to warm to room temperature. The reaction mixture was partitioned between ether and water, and the organic layer was washed with saturated aqueous NaCl and dried (MgSO4). Evaporation at reduced pressure gave a yellow solid which was added to 25 ml of 3N HCl and heated at reflux for 3 hours. After cooling to room the pH of the solution was adjusted to pH 7, and the solution was extracted twice with methylene chloride. The combined organic phases were washed with water and dried (MgSO4). Evaporation at reduced pressure gave a yellow oil which was Kugelrohr distilled to yield 3.8 g (80%) of the desired product as a liquid, bp 91°-93° C. (0.1 mm). IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)=[O:6].[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[OH:6][CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1coc(Cc2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC(O)c1coc(Cc2ccc(F)cc2)c1
Reaction time: 15 h

Procedure:
46.5 ml of a 1.5M solution of vinylmagnesium chloride in tetrahydrofuran are initially taken in 60 ml of absolute tetrahydrofuran at 0° C. 11.9 g of 3-formyl-5-(p-fluorobenzyl)-furan in 60 ml of absolute tetrahydrofuran are added dropwise at 0°-10° C. to the stirred mixture in the absence of moisture, and stirring is continued for 15 hours at room temperature. 100 ml of a saturated ammonium chloride solution and 20 ml of glacial acetic acid are added carefully to the reaction mixture, the precipitate dissolving. The mixture is extracted three times by shaking with ether, after which the combined ether extracts are washed with water, dried over sodium sulfate and evaporated down under reduced pressure. The oil obtained (14 g) is purified by column chromatography over silica gel using toluene/acetone (9/1) as the eluent. 7.1 g of 3-(1-hydroxy-2-propenyl)-5-(p-fluorobenzyl)-furan are obtained as an oil (nD22 : 1.5370). ##STR15##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[CH:26][CH:27]=[CH:28][C:15]3=4)[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:32][O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1>>[CH:24]1[C:19]2[CH:18]=[CH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[CH:14]([C:12]3[C:11](=[O:29])[NH:10][C:9](=[O:30])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:36]5[CH2:37][CH2:38][CH2:39][C@H:35]5[C:34]([O:33][CH3:32])=[O:40])[N:7]=4)[CH:13]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c(=O)n(-c2ccnc(Cl)n2)cc1C1c2ccccc2C=Cc2ccccc21
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1nccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 6 step (i) (0.3 g) and L-proline methyl ester hydrochloride (0.6 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5% methanol in dichloromethane. Yield 0.55 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C1([Si:16]2([CH2:31][CH2:32][CH2:33][CH:34]([F:36])[CH3:35])[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=CC=CC=1>>[F:36][CH:34]([CH3:35])[CH2:33][CH2:32][CH2:31][Si@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[O:27])=[CH:29][CH:30]=2)[CH2:18][CH2:17]1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1ccc(F)c(F)c1
Product: CC(F)CCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-difluorophenol and 4-(4-phenyl-4-(4-fluoropentyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)[CH3:2]>Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)N1CCC(CCCC(=O)c2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 161.6 %

Procedure:
A solution of 1-acetyl-4-[3-(4-fluorobenzoyl)propyl]piperidine(1.7 g) in concentrated hydrochloric acid (15 ml) was refluxed for 16 hours and the hydrochloric acid was then distilled off under reduced pressure. The residue was dissolved in water and the solution was made weakly basic (pH ca.8) with 5% aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off to recover 1.3 g of residue. To a solution of this residue (1.3 g) in ethanol (10 ml) was added 0.94 g of potassium carbonate and 0.9 g of benzyl bromide was added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 hours and then filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with dichloromethane and the extract was washed with water and dried over anhydrous sodium sulfate. Finally the solvent was distilled off to give 1.6 g of 1-benzyl-4-[3-(4-fluorobenzoyl)propyl]piperidine melting at 53°-55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:24]=[CH:23][C:22]=1O>>[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)CCc1cc(C(=O)c2cccc(C#N)c2)ccc1O
Reactant: COc1ccc(C=CCCCCO)cc1
Product: COC(=O)CCc1cc(C(=O)c2cccc(C#N)c2)ccc1OCCCCC=Cc1ccc(OC)cc1
Yield: 34.1 %

Procedure:
Following the general procedure of Example 92B, 1.63 g of 6-(4-methoxyphenyl)-5-hexenyl alcohol were converted to its mesyl ester and reacted with 2.45 g of 5-(3-cyanobenzoyl)-2-hydroxybenzenepropanoic acid methyl ester to provide 1.34 g of 5-(3-cyanobenzoyl)-2-{[6-(4-methoxyphenyl)-5-hexenyl]oxy}benzenepropanoic acid methyl ester, m.p. 65°-67° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:8].[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][N:13]1[CH2:12][CH:11]([OH:23])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:24]=[C:2]([NH:31][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[CH:3]=[N:4][CH:5]=1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cncc(Br)c1
Reactant: NC1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cncc(NC2CCOCC2)c1
Temperature: 110 °C
Yield: 24.3 %

Procedure:
To a solution of 5-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)nicotinamide (100 mg, 0.26 mmol) in dioxane (10 mL) were added tetrahydro-2H-pyran-4-amine (39.4 mg, 0.29 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), NaOtBu (24 mg, 0.52 mmol) and BINAP (26 mg, 0.04 mmol). The reaction mixture was heated at 110° C. for 6 h under N2. The mixture was concentrated and the residue was dissolved in EA, washed with water, the organic layer was collected, dried, and the residue purified by prep-HPLC to give the title compound (25.9 mg, Yield 24%). 1H NMR (CD3OD, 400 MHz): δ 8.17 (d, J=1.5 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.43-7.35 (m, 1H), 7.13-7.06 (m, 3H), 7.04-6.99 (m, 1H), 4.17-4.07 (m, 1H), 4.02-3.93 (m, 2H), 3.73 (s, 2H), 3.63-3.50 (m, 4H), 3.41 (dd, J=6.8, 13.6 Hz, 1H), 2.94-2.82 (m, 4H), 2.70-2.57 (m, 2H), 2.03-1.93 (m, 2H), 1.57-1.45 (m, 2H). LCMS (m/z): 411.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-t-butyl-2-iodophenol [38941-98-9] (1.0 g, 3.6 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give 84 as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Pyridin-4-ylmethanol (4.0 g, 37 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (11.21 g, 111 mmol) was added to the reaction mixture. The solution was cooled to 0° C. and methanesulfonyl chloride (MsCl) (6.3 g, 55.5 mmol) was added slowly. After the addition was complete, the reaction was stirred at 0° C. for 15 min and then stirred at room temperature for 2 hours. Water was slowly added and the solution was extracted with dichloromethane. The organic layer was washed with brine, and dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol, and activated charcoal was added. After the mixture was stirred for 1 hour the mixture was filtered through a plug of celite and concentrated in vacuo to afford pyridine-4-ylmethyl methanesulfonate (49).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(F)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[C:16]([Cl:17])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A mixture of 20 g 2,4-dichloro-5-fluoropyrimidine, 22.86 g 3,4-dichlorophenylboronic acid, 33.11 g potassium carbonate and 6.92 g tetrakis(triphenylphosphine)palladium were in 500 mL THF and 500 mL water was heated to reflux for 4 h. The reaction mixture was cooled to room temperature diluted with water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with dichloromethane to yield 24.640 g (74.13%) of the title compound as white solid, MS 279.1 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([CH:31]=[N:32]O)=[C:29]([CH3:34])[N:28]=[C:27]([CH:35]([CH3:37])[CH3:36])[C:26]=2[CH2:38][OH:39])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[C:31]([C:30]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:26]([CH:38]=[O:39])[C:27]([CH:35]([CH3:37])[CH3:36])=[N:28][C:29]=1[CH3:34])#[N:32]
Reactant: Cc1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1C=NO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C#N
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4.4 g (21 mmol) of trifluoroacetic anhydride in 15 ml of methylene chloride are added dropwise at -78° C. to 1.1 g (14 mmol) of DMSO in 8 ml of methylene chloride p.A. and the mixture is stirred for 10 minutes at -70° C. 2.1 g (7 mmol) of compound 2 from Example 143 are then added in 50 ml of methylene chloride, the mixture is stirred for 1 h at -70° C. 5.8 ml (42 mmol) of triethylamine are now added and the mixture is stirred for 4 h at room temperature. It is washed with saturated sodium chloride solution, concentrated, chromatographed over 100 g of silica gel (230-400 mesh, φ 4 cm, petroleum ether/ethyl acetate 10:1) and recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH:10]=1)=[O:6].Cl>COCCO.O1CCOCC1>[ClH:22].[Cl:22][C:21]1[CH:20]=[N:19][C:18]2[NH:1][C:2]3[CH:26]=[CH:25][CH:24]=[C:4]([CH:3]=3)[C:5](=[O:6])[NH:7][CH2:8][C:9]3[CH:10]=[C:11]([NH:15][C:16]=1[N:17]=2)[CH:12]=[CH:13][CH:14]=3
Reactant: Nc1cccc(C(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: O=C1NCc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C
Yield: 62.5 %

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzamide (80.0 mg, 0.206 mmol) in 2-methoxyethanol (1.1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (154 μL). The resulting mixture was heated at 150° C. in a microwave for 15 min. The cloudy mixture was filtered. The crude cake was recrystallized from MeOH to give the desired product as an off-white powder (25 mg, 34%). LCMS for C18H14ClN5O (M+H)+: m/z=352.0. 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.50 (t, J=2.0 Hz, 1H), 9.05 (t, J=2.0 Hz, 1H), 8.24 (m, 1H), 7.86 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.28 (m, 2H), 7.10 (t, J=7.6 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][C:13]4[C:15](=O)[CH2:16][CH2:17][CH2:18][C:12]=4[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][C:13]4[CH:15]([NH2:28])[CH2:16][CH2:17][CH2:18][C:12]=4[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCCc2c1sc1ccc(-c3ccccc3)cc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2c1sc1ccc(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 22.9 %

Procedure:
To a solution of 8-phenyl-2,3-dihydrodibenzo[b,d]thiophen-4(1H)-one (0.28 g, 1.0 mmol, 1 eq), ammonium acetate (0.77 g, 10 eq) in MeOH (20 mL) was added NaBH3CN (160 mg, 2.5 eq) in one portion. The reaction mixture was heated to 50° C. and stirred for 20 h, After that the solvent was removed, diluted with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the title compound (64 mg, 23%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[C:17]([CH2:18][CH:19]2OCCO2)=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:15]([CH:31]([CH3:33])[CH3:32])[N:14]=1)C1C=CC=CC=1.Cl.N#N>[Pd].C(O)(CC)(C)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[N:15]([CH:31]([CH3:33])[CH3:32])[N:14]=[C:13]3[C:17]=2[CH2:18][CH2:19][NH:10][CH2:11][CH2:12]3)=[CH:25][CH:26]=1
Reactant: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CCC(C)(C)O
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 2.2 L Parr hydrogenation flask was added {2-[4-[1,3]dioxolan-2-ylmethyl-5-(4-fluoro-phenyl)-1-isopropyl-1H-pyrazol-3-yl]-ethyl}-carbamic acid benzyl ester (90.0 g, 0.193 mol), t-amyl alcohol (910 mL), and 3 N HCl (190 mL, 0.570 mol). The flask was charged with N2(g) and 10% Pd/C (22.2 g) was added. The reaction mixture was hydrogenated at 40 psi and at 45° C. for 18 h. The mixture was filtered through acid-treated, low metal filter paper. The filtrate was concentrated to oil, diluted with water (500 mL), and washed with EtOAc (3×250 mL). The aqueous mixture was cooled to 0° C. and basified to pH 13-14 by the addition of KOH pellets. The aqueous solution was extracted with EtOAc (3×250 mL). The combined organic layers were filtered through acid-treated filter paper. The filtrate was dried (Na2SO4) and concentrated to give the title compound. MS (ESI): exact mass calcd. for C16H20FN3, 273.16; m/z found, 274.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.25-7.20 (m, 2H), 7.18-7.13 (t, J=8.6, 2H), 4.28-4.21 (sept, J=6.6, 1H), 3.04-3.01 (m, 2H), 2.94-2.88 (m, 4H), 2.46 (t, J=5.2, 2H), 1.40 (d, J=6.6, 6H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:54])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:44][C:41]1[CH:40]=[CH:39][C:38]([S:35]([CH:26]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:23]([C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:54])[NH:17][C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[C:9]([OH:10])=[O:8])[CH:24]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:25]2)(=[O:37])=[O:36])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccc(N)cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Temperature: 20 °C
Yield: 66.4 %

Procedure:
A To a solution of 1.7 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(4-nitrophenyl)sulphonyl-2-pyrrolidinecarboxylate in 100 cm3 of ethanol is added 0.2 g of 10% palladium-on-charcoal. The suspension is stirred for twenty hours at a temperature in the region of 20° C. under a hydrogen atmosphere (130 kPa). The catalyst is separated out by filtration on Celite and the filtrate is concentrated to dryness under reduced pressure. The residue is purified by chromatography on 40 g of silica contained in a column 2.2 cm in diameter [eluent: dichloromethane/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 0.95 g of (2RS,4SR,5RS)-3-(3-{2-[4-(4-aminophenyl)sulphonyl-2-tert-butoxycarbonyl-5-(2-fluorophenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is thus obtained [Rf=0.2; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.55 (s, 9H: C(CH3)3); from 2.30 to 2.55 and 2.76 (2 mts, 1H each: CH2 at 3); 3.68 and 4.00 (broad d and d respectively, J=17 Hz, 1H each:COCH2N); 3.84 (mt, 1H: H4); 4.62 (t, J=8 Hz, 1H: H2); 5,72 (d, J=3 Hz, 1H: H5); 6.76 (d, J=8 Hz, 2H: H of the aromatic at 4 (H ortho to the NH2)); 7.00 to 7.70 (mt, 6H: aromatic H); 7.58 (d, J=8 Hz, 2H: H of the aromatic at 4 (H meta to the NH2)); 7.82 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.00 (t, J=1.5 Hz, 1H: aromatic H (H2: ortho to the COOH))].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.C([Li])CCC.[CH:20](=[O:23])[CH2:21][CH3:22].O>COC(C)(C)C.CCCCCC>[CH3:14][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([CH:20]([OH:23])[CH2:21][CH3:22])=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1ccc(Br)cn1
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: COC(C)(C)C
Product: CCC(O)c1ccc(-n2c(C)ccc2C)nc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 2 g of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine in 30 mL of tert-butyl methyl ether cooled to −78° C. are added slowly, under argon, 3.3 mL of a 2.5M solution of butyllithium in hexane, the mixture is then stirred for 40 minutes at about −70° C., followed by addition of a solution of 0.5 g of propionaldehyde in 5 mL of tert-butyl methyl ether. The mixture is stirred for 30 minutes at about −70° C., 20 mL of water are then added slowly and the resulting mixture is allowed to warm to 20° C. The aqueous phase is extracted with twice 100 mL of ethyl acetate and the organic phases are combined, dried and concentrated to dryness. The residue is purified by flash chromatography on a cartridge of 70 g of silica, eluting with dichloromethane and then with an 80/20 mixture of dichloromethane and ethyl acetate. The fractions containing the expected product are combined and concentrated under vacuum to give 1.07 g of 1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]propan-1-ol in the form of a yellow oil.