Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:3]([P:15]([OH:18])(=[O:17])[OH:16])([P:11]([OH:14])(=[O:13])[OH:12])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH:7]=[CH:6]2>O=[Pt]=O.O>[SH:1][CH:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][NH:9]2)[CH2:4][C:3]1([P:15]([OH:18])(=[O:16])[OH:17])[P:11]([OH:13])(=[O:12])[OH:14]
Reactant: O=P(O)(O)C1(P(=O)(O)O)C=C2C=CCNC2=C1S
Agent: O=[Pt]=O
Solvent: O
Product: O=P(O)(O)C1(P(=O)(O)O)CC2CCCNC2C1S

Procedure:
Dihydro-7-mercapto-1-pyrindine-6,6-bisphosphonic acid (0.5 mmol) [prepared as described in Example A hereinbefore], distilled water (100 ml) and PtO2 (0.5 g) are placed in a 500 ml Parr hydrogenation bottle. The mixture is hydrogenated at room temperature (40 psi) for 48 hours. The solution is filtered through celite and washed with hot water. The filtrate is then concentrated under reduced pressure and the desired product is obtained in good purity by further drying the resultant solid overnight under vacuum.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C@H:8]1[O:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([Si:5]([CH3:15])([CH3:14])[O:6][CH2:7][C@H:8]1[O:12][C:11](=[S:25])[CH2:10][CH2:9]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=S)O1
Yield: 57.1 %

Procedure:
The title compound is prepared by the procedure of Example 353 using 0.868 g of product from Example 359, 10 ml of toluene and 0,763 g of Lawesson's Reagent to give 0.530 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: Nc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
In ethanol (100 ml) was dissolved 1—(3-nitrobenzyl)-piperidine (32.2 g), and to the mixture was added dried 10% palladium on carbon (1.61 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from diisopropylether-hexane to give 1—(3-aminobenzyl)piperidine (15.8 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:11])[NH:24][N:23]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: NN
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccc(C(F)(F)F)c2)c2ncccc12

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and hydrazine hydrate (0.4 g) in ethanol was heated at the reflux temperature for 5 hours. On cooling and reduction of the volume of solvent by evaporation, a precipitate formed which was collected by filtration, to give the title compound as a white solid, 1.08 g, m.p. 210°-215° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:33]2[O:34][C:35]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:36][C:37](=[O:39])[CH:38]=2)=[CH:10][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Cc1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Temperature: 100 °C

Procedure:
[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-1-yl]-carbamic acid tert-butyl ester (2.90 g, 6.50 mmol) was introduced to a solution of 2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(1.4 g, 6.50 mmol) in anhydrous dioxane (6 mL). Powdered K2CO3 (2.01 g, 14.50 mmol) was added and the mixture degassed (sonication for 20 mins then saturated with N2). To the degassed solution was added Tetrakis (triphenylphosphine) palladium (0.39 g) before it was degassed for a further 20 minutes. A reflux condenser was attached to the reaction vessel which was submerged into an oil bath maintained at 100° C. for 14 hours whereupon the golden mixture was cooled and diluted with EtOAc (50 ml) and then washed with water (20 ml) and saturated brine (20 ml). Organic extract was dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a light brown oil that was used without further purification. m/z (LC-MS, ESP): 493 [M+H]+, R/T=4.41 mins.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]2[S:11][C:12](=[O:17])[NH:13][C:14]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 31.7 %

Procedure:
4-Methoxybenzaldehyde (20.4 g, 150 mmol), thiazolidine-2,4-dione (21.1 g, 180 mmol), piperidine (12.8 g, 150 mmol) and ethanol (150 mL) were mixed and refluxed for 18 hours. After allowed to stand for cooling, the precipitated crystals were collected by filtration. These were washed with ethanol, and then dried to obtain 11.2 g (32%) of the title compound as yellow crystals. Moreover, the filtrate was made acidic with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to additionally obtain 18.1 g (51%, totally 83%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1ncc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
12.0 g (18.1 mmol) of 2-n-butyl-4-chloro-1-[(2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde in 150 ml of methanol are hydrogenated at 25° C. for 1.5 h at a hydrogen pressure of about 3 bar in the presence of 1. 2 g of palladium on active carbon (5%) and 2.46 g (18.1 mmol) of sodium acetate trihydrate. The solution is then filtered off from the catalyst and concentrated, and the residue is chromatographed on silica gel 60 using ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.Br.C(Cl)Cl.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:23][CH2:22]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([O:30][CH2:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[CH:32][CH:33]=2)[N:6]=1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(OCCCN2CCOCC2)cc1
Agent: Br
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(OCCCN4CCOCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-Fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10, 140 mg, 0.6 mmol) was dissolved in dry NMP (2 ml) and 4-(3-morpholinopropoxy)aniline.2.HBr salt (see CAS Registry No. 100800–40–6; J.Am.Chem.Soc., 76, 1954, 4396; 188 mg, 0.5 mmol) added. The mixture was stirred at ambient temperature for 5 minutes, then checked to ensure the reaction mixture was acidic (pH 1) and heated at 100° C. for 3 hours. The mixture was allowed to cool and evaporated to dryness to give an oil. Silica (2 g) and DCM (10 ml) were added and the mixture then re-evaporated to dryness and purified by chromatography on a Mega Bond Elute column (10 g) (eluting with DCM (2×25 ml), 2% NH3 in MeOH (3×25 ml), 4% NH3 in MeOH (3×25 ml), 6% NH3 in MeOH (3×25 ml), 10% NH3 in MeOH (9×25 ml)) to give the title product as a colourless oil, which was triturated with diethyl ether to give a white solid (95 mg, 46%). NMR (300 MHz): 1.8 (m, 2H), 2.2 (s, 3H), 2.4 (m, 4H), 2.4 (m, 2H), 3.6 (t, 3H), 3.9 (t, 2H), 6.2 (d, 1H), 6.8 (d, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.5 (d, 2H), 7.8 (d, 1H), 8.0 (d, 1H), 8.9 (s, 2H); m/z: (ES+) 438.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([C:21]#[C:22][Si](C)(C)C)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.C1C(=O)N([Br:35])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([C:21]#[C:22][Br:35])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#C[Si](C)(C)C)c(C)cc(Br)c32)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C#CBr)c(C)cc(Br)c32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-bromo-5-methyl-1-tosyl-4-((trimethylsilyl)ethynyl)-1H-indole (70 mg, 0.152 mmol) and AgNO3 (7.75 mg, 0.046 mmol) in acetone (0.8 mL) at 0° C. was added a solution of NBS (38 mg, 0.213 mmol) in acetone (0.8 mL) and the mixture was warmed to room temperature. After stirring overnight the reaction was purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=3.79 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H) 7.37-7.48 (m, 3H) 6.91 (d, J=3.79 Hz, 1H) 2.38 (s, 3H) 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([N:62]3[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]3)=[O:20])[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)c2cccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a dichloromethane (5 ml) solution of 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid (130 mg, 0.307 mmol) were added N-methylmorpholine (41 μl, 0.368 mmol), 1-hydroxybenzotriazole (13 mg, 0.368 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.368 mmol) and 1-methylpiperazine (40 μl, 0.368 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give the title compound (40 mg, 0.0791 mmol, 26%) as a white amorphous substance.
Reaction SMILES: C[Si]([Br:5])(C)C.N(OC(C)(C)C)=O.N[C:14]1[S:15][C:16]2[C:21](=[O:22])[N:20]=[C:19]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:18][C:17]=2[N:29]=1>C(#N)C>[Br:5][C:14]1[S:15][C:16]2[C:21](=[O:22])[N:20]=[C:19]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[NH:18][C:17]=2[N:29]=1
Reactant: CCCCCSc1nc(=O)c2sc(N)nc2[nH]1
Reactant: C[Si](C)(C)Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCCCCSc1nc(=O)c2sc(Br)nc2[nH]1
Reaction time: 0.5 h

Procedure:
Trimethylsilyl bromide (0.44 mL) was added slowly to a solution at 0° C. under nitrogen of us t-butyl nitrite (0.42 mL) in acetonitrile (2 mL). After 30 minute at 0° C., 2-amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one (0.5 g) (product of Example 10) was added.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:16])([F:15])[C:6]([C:8]1[C:9](F)=[N:10][CH:11]=[CH:12][CH:13]=1)=O>C(O)C>[F:4][C:5]([F:16])([F:15])[C:6]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:3][N:2]=1
Reactant: NN
Reactant: O=C(c1cccnc1F)C(F)(F)F
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1n[nH]c2ncccc12
Yield: 84.9 %

Procedure:
Hydrazine hydrate (3.06 mL, 63.0 mmol) was added to 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (1.9 g, 9.0 mmol) in absolute ethanol (50 mL), and the mixture was heated to reflux overnight. The cooled reaction mixture was evaporated to afford a solid, which was partitioned between water and ethyl acetate. The aqueous layer was extracted with another portion of ethyl acetate. The combined ethyl acetate extracts were washed twice with brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (1.43 g, 85%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C@@H:12]2[CH2:11][O:10][C:9]([C:3]3[C:2]([F:1])=[C:7]([C:22]#[C:21][CH2:20][OH:23])[CH:6]=[CH:5][CH:4]=3)=[N:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1c(I)cccc1C1=N[C@H](c2ccccc2)CO1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 4,5-dihydro-2-(2-fluoro-3-iodophenyl)-4(R)-phenyloxazole (2.28 g, 6.2 mmol), propargyl alcohol (0.22 g, 12.4 mmol) and bis(triphenylphosphine)-palladium(II) chloride (220 mg, 1.1 mmol) in triethylamine (50 ml), was stirred for 1 h under a nitrogen atmosphere, Cul (420 mg, 2.2 mmol) added and the reaction mixture stirred for a further 16 hours. Insoluble material was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:14) to afford of 3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluorophenyl]-2-propyn-1-ol (1.41 g, 77%) as off-white solids.
Reaction SMILES: C(OC(=O)[N:7]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=1[Cl:45])[CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:45][C:36]1[C:37]([C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:19]([CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:17][CH2:16][O:15][NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: Cc1ccc(N(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NOCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of {3-[(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl-amino)]-propoxy}-4-methyl-phenyl carbamic acid tert-butyl ester (0.09 g, 0.14 mmol) and CH2Cl2 (2 mL), TFA (0.20 mL, 1.2 mmol) was added and the reaction mixture was stirred for 1 h. The mixture was then poured into NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated to yield the product as a yellow oil (0.03 g, 39%): MS(ES) m/e 553.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=O)[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[S:22])[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Solvent: c1ccncc1
Product: O=C1CC(=S)Nc2ccccc2N1Cc1ccccc1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A solution of 1-benzyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (160 mg, 0.60 mmol) and P2S5 (140 mg, 0.63 mmol) in 20 mL of pyridine was heated to reflux and stirred for 1 h under N2 atmosphere. The solvent was evaporated in vacuo, the residue was purified by prep-TLC (DCM:MeOH=50:1) to give 1-benzyl-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (50 mg, 30%). 1H NMR (300 MHz, DMSO): δ 3.74 (q, J=12.3 Hz, J=12.3 Hz, 1H), 5.12 (q, J=15.6 Hz, J=15.9 Hz, 1H), 7.03-7.06 (m, 2H), 7.17-7.27 (m, 6H), 7.48 (d, J=7.5 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]([OH:18])=[O:17]>C(Cl)(Cl)Cl>[C:1]([C:14]1[S:10][C:11]([CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)Cc1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc(C(=O)c2ccccc2)s1
Yield: 50 %

Procedure:
Using the procedure of Example 1, 8.45 gm of benzoyl chloride, 7.1 gm of thiophene-2-acetic acid [prepared by process of Cagniant, Bull. Soc. Chim., 1949, p.847] and 18 gm aluminum alumina chloride suspended in chloroform were reacted to obtain, after crystallization, a 50% yield of 5-benzoyl-thiophene-2-acetic acid melting at 144° C. The product occurred in the form of colorless crystals insoluble in water.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62][CH:61]=1>ClCCl>[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:62][CH:61]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: COC(=O)c1ccc(N)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (as prepared in Example 45, 200 mg, 0.62 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (345 mg, 0.74 mmol), N,N-diisopropylethylamine (240 mg, 1.85 mmol) and 6-aminonicotinic acid methyl ester (115 mg, 0.74 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester (57 mg, 20%) as a light yellow solid: LR-ES-MS m/z calculated for C23H23F2N3O5 [M]+ 459, observed [M+H]+ 460; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H) 0.94 (d, J=6.9 Hz, 3H) 1.39-1.74 (m, 2H) 1.73-1.92 (m, 1H) 3.86 (s, 3H) 4.32 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.95-5.05 (m, 1H) 5.06 (s, 1H) 7.25-7.53 (m, 3H) 8.17 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.34 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].[K+].C([OH:38])(C)(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:24])=[O:38])=[N:21][CH:22]=3)[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C#N)nc2)n1)c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(C(N)=O)nc2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To 38 mg of (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}picolinonitrile, was added t-butanol, and 60 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 90° C. for 4 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a solution of ii (770 g, 3.53 mol) in acetone (10 L) was added K2CO3 (2.45 kg, 17.75 mol) at RT followed by benzyl bromide (632 mL, 5.32 mol) over a period of 30 min. The mixture was stirred for 15 min and then heated at reflux for 3 h. The mixture was filtered through celite and the acetone was distilled off. The residue was purified over silica eluting with EtOAc:hexane (5:95) to obtain iii (551 g, 51%).