Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:9](=[O:20])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)(=O)C>[C:1]1([CH:7]2[CH2:8][C:9](=[O:20])[N:10]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)N1c1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)CC(=O)N1C1CCNCC1
Reaction time: 8 h

Procedure:
The mixture of 14.6 g of 4-phenyl-1-(4-pyridyl)-piperidin-2,6-dione, 12.3 g of 10% palladium on carbon and 200 ml of glacial acetic acid is hydrogenated at 1.7 atm. and 100° for 8 hours. After cooling, the mixture is filtered, evaporated, the residue dissolved in the minimum amount of water and the solution basified with sodium carbonate. It is extracted with ethyl acetate, the extract evaporated and the residue crystallized by trituration with 75 ml of diethyl ether-hexane (3:1) and recrystallized from 50 ml of isopropanol to yield the 4-phenyl-1-(4-piperidinyl)-piperidin-2,6-dione melting at 182°-189°; its p-methoxyphenyl analog melts at 127°-129°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1[C:21]2[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][NH:17][CH2:16][C:15]=2[S:14][CH:13]=1>N1C=CC=CC=1.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:17]2[CH2:16][C:15]3[S:14][CH:13]=[CH:12][C:21]=3[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2n(c1)-c1ccsc1CNC2
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3sccc3-n3cccc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
An excess of para-toluenesulfonyl chloride is added to a solution of 1 g (0.0053 mol) of 5,6-dihydro -4H-pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine in 10 ml of pyridine, and the reaction mixture is then stirred at room temperature for one hour. The pyridine is then removed under reduced pressure and the oil residue obtained is ground in 100 ml of water. The emulsion formed is extracted with 3 times 100 ml of ethyl ether. The organic phases are separated after settling has taken place, combined, dried, washed with acidulated water, dried over magnesium sulfate and evaporated under vacuum. The solid residue is recrystallized. 0.4 g of 5-(p-tolylsulfonyl)-5,6-dihydro-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is thereby obtained in the form of yellow crystals, melting point 165° C. (ethyl ether).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[CH:28][CH:27]=2)[C:31]([OH:33])=[O:32]
Reactant: OCCCNc1ccccn1
Reactant: COC(=O)C(C)Cc1cc2cc(O)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.13 g, 0.57 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)-2-methylpropanoate (0.062 g, 0.27 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.06 g, 0.40 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.11 g, 0.53 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.015 g, 15%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.41 (m, 1H), 4.89 (br s, 1H), 4.45 (dd, J=14.2, 7.3 Hz, 1H), 4.10 (m, 4H), 3.63 (s, 3H), 5.52 (q, J=6.5 Hz, 2H), 2.13 (m, 2H), 1.66 (m, 1H), 1.52 (m, 1H), 1.16 (d, J=7.1 Hz, 3H), 0.93 (m, 3H).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]3[C:12]([CH2:13][O:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[N:23]=2)[CH2:18][CH2:17]1>CC(O)(C)C>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]3[C:12]([CH2:13][O:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:29])=[O:1])[N:23]=2)[CH2:20][CH2:21]1
Reactant: N#Cc1cccc(N2CCC(c3nnc4n3-c3ccc(Cl)cc3COC4)CC2)n1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cccc(N2CCC(c3nnc4n3-c3ccc(Cl)cc3COC4)CC2)n1
Temperature: 100 °C
Yield: 54 %

Procedure:
Powdered potassium hydroxide (46 mg, 81 mmol) was added to a solution of the carbonitrile of example 20 (110 mg, 0.27 mmol) in 2-Methyl-propan-2-ol (6 ml). The mixture was heated at 100° C. for 18 hours before evaporation under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound (62 mg), as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C>CCOC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(F)c1
Agent: C
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(F)c1
Yield: 87.5 %

Procedure:
Prepared from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile and 2.86 g of 3-fluoroaniline in the same manner as EXAMPLE 377. The crude product was dissolved in a large volume of EtOAc, treated with Darco and filtered through Celite. Solvent removal and drying in vacuo (50° C.) gave 5.77 g of 4-(3-fluorophenylamino)-6-nitroquinoline-3-carbonitrile as a yellow-orange solid: mass spectrum (electrospray, m/e): M+H 309.2.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:22](=[CH:23][CH:24]=1)[O:21][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:25].Cl>CC(O)=O>[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:11]2([CH2:10][C:9](=[O:25])[C:8]3[C:22](=[CH:23][CH:24]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])[CH:7]=3)[O:21]2)[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 98.8 %

Procedure:
(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (500 mg, 1.40 mmol) was hydrolyzed with HCl and AcOH following the procedure described in Example 22, Step A, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid as a white solid (475 mg, 98.9%). The acid was treated with NH2OTHP according to the procedure described in Example 22, Step C, giving (E)-3-[1-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (416 mg, 69.7%). Finally, removal of THP protecting group following the procedure described in Example 23, Step D gave (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-N-hydroxy-acrylamide (43 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1cccc1Cc1ccc(N)cc1
Yield: 99.9 %

Procedure:
4-(1-Methylpyrrol-2-ylmethyl)nitrobenzene (500 mg, 2.31 mmol) [prepared as described in Example 21, Step (b)], was dissolved in ethyl acetate and subjected to hydrogenation over 5% Pd/C (50 mg) at ambient temperature and atmospheric pressure. After 3 h the mixture was filtered and the filtrate was concentrated to give 4-(1-methylpyrrol-2-yl-methyl)aniline (430 mg, 100%) as a yellow oil. ##STR64##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:29])C(=O)C1>>[Cl:29][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.30 g, 1.05 mmol) and NCS (0.17 g, 1.26 mmol) according to method C to yield 0.21 g (62%) of a light orange solid: mp 126–128° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.25–7.31 (1H, m), 7.35 (1H, d, J=8.91 Hz), 7.64–7.67 (1H, m), 7.70–7.78 (2H, m), 7.87 (1H, dd, J=1.58 Hz, J=9.04 Hz), 10.68 (1H, s); MS (ESI) m/z 319/321 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)ccc1OC
Yield: 75.4 %

Procedure:
To a solution of 52.0 g (0.25 mole) of this ketone in 400 ml of chloroform is added a solution of 40.0 g (0.25 mole) of bromine in 200 ml of chloroform at such a rate as reaction mixture decolorizes (50 minutes after a 25 minute initiation period). Solvent is evaporated and the residue recrystallized from methanol to give 54.1 g (75%) of methyl 5-(2-bromoacetyl)-2-methoxybenzoate, m.p. 149°-153° C. A second crop of 10.4 g is obtained from the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: CC(C)n1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, MS: (neg. ions): m/e=334.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.Cl>CC(O)C>[ClH:1].[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2ccnc3ccccc23)cc1

Procedure:
To a suspension of 4-chloroquinoline (0.500 g, 3.06 mmol) and 4-aminobenzoic acid (0.419 g, 3.06 mmol) in 2-propanol (10 mL) 3 drops of concentrated hydrochloric acid were added and mixture was microwave irradiated at 150° C. for 1 hour. After cooling solid was filtered off, washed with 2-propanol and dried in vacuo to give Cpd C as a yellow powder. Purity (HPLC): 100%. 1H NMR (DMSO-d6): 7.05 (d, J=6.9 Hz, 1H), 7.64-7.67 (m, 2H), 7.80-7.85 (m, 1H), 8.02-8.17 (m, 5H), 8.59 (d, J=7.2 Hz, 1H), 8.92 (d, J=8.1 Hz, 1H), 11.26 (s, 1H). MS (ES+): calc. for C16H13N2O2 (MH+) 265.1, found 265.1.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:18])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Cl:2][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:15][CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(CCC(=O)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CC=C(Cl)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a refluxing mixture of phosphorus pentachloride (5.8 g) and carbon tetrachloride (25 ml) is slowly added m-phenoxybenzyl 3-benzoylpropionate (5 g) in carbon tetrachloride (10 ml) over about 45 minutes. Refluxing is continued about 0.5 hr and then the reaction is poured onto ice and extracted with ether. The ether extracts are combined, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried over calcium sulfate and solvent evaporated. The product is subjected to prep. TLC using 12% ethyl acetate/hexane and the major band collected to yield m-phenoxybenzyl 4-chloro-4-phenyl-3-butenoate.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1)=O)C.O.[NH2:33][NH2:34].Cl.CO>C(O)(=O)C>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][CH:5]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:4](=[O:3])[NH:33][N:34]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(CC(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1CCCOc1ccc(C2=NNC(=O)C(c3ccccn3)C2)cc1

Procedure:
In a 50 mL round bottom flask, 4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-2-pyridin-2-yl-butyric acid ethyl ester (950 mg, 1.84 mmol), and hydrazine monohydrate (204 μL, 4.2 mmol), in acetic acid (20 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and NaHCO3 sol., extracted three times, and then dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 250 mg (33%). Ethereal HCl was added to a methanol solution to produce crystals. Mp 231-233° C. MS m/z 393 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH:9]([OH:14])[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(c1c(Br)cccc1Br)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1c(Br)cccc1Br)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanone (CAS#1208078-23-2) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH4 (340 mg, 9 mmol) at 5° C. The reaction was warmed to RT for 1 h, then extracted with EtOAc NaHCO3, brine, and dried over Na2SO4 filtered and concentrated in vacuo to provide 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[C:10]3([C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3([CH3:19])[CH3:18])[O:9]2)[CH:7]=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[C:10](=[O:9])[C:11]([CH3:19])([CH3:18])[O:12][C:13]([CH3:16])([CH3:17])[C:14]2=[O:15])[CH:7]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2F)C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 2-(5-bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.60 g, 19.30 mmol) in dichloromethane (8 ml) is added a second ice-cold solution of concentrated sulphuric acid (13.8 ml) dropwise, maintaining temperature below 5° C. The reaction mixture is stirred for a further 30 minutes, then quenched with distilled water (50 ml). After stirring for an additional 10 minutes the organics are removed in vacuo, and the resulting precipitate is filtered then triturated with water. After washing with hexanes the solid is dried to afford 4-(5-bromo-2-fluorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (4.30 g, 65%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>Cl.CO>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Obtained from Intermediate 21 (0.167 g, 1.42 mmol) in hydrogen chloride 1.25M in methanol by the same procedure described in Intermediate 17. The solvent was removed to give the title compound as a white solid salt (0.127 g, 98%), which was used in the next step without further purification. MS (M+): 300.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:23]=3[C:22]([CH3:31])([CH3:30])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:31])([CH3:30])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2cnc(Oc3ccccc3)cc21
Temperature: 100 °C
Yield: 0 %

Procedure:
(2R,5R)-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mol), phenol (24 mg, 0.206 mol), K3PO4 (96 mg, 0.43 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (3 mg, 0.01 mmol), Pd(OAc)2 were combined and slurried in toluene (0.714 mL). The reaction was degassed with nitrogen and heated to 100° C. After 18 h the reaction was cooled to RT. MeOH was added and the solution passed through a Phenomenex NH2 column, eluting with MeOH and then 2.0 M ammonia in MeOH to release the amine. The residue was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give (75 mg). Further purification by preparative HPLC (basic method), gave the title compound (19 mg, 17%) as a colourless oil. 1H NMR (Me-d3-OD): 7.91 (1H, s), 7.51 (1H, s), 7.42 (2H, t), 7.22 (1H, t), 7.10 (2H, d), 4.22-4.12 (1H, m), 4.05 (2H, q), 3.95 (1H, d), 3.70 (1H, d), 3.60 (1H, dd), 3.52 (1H, d), 3.00 (1H, s), 2.85 (1H, dd), 2.64 (1H, dd), 1.48 (9H, s), 1.43 (6H, s), 1.22 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[CH:6]=1)[CH2:26][CH:25]=[CH2:24]
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Reactant: C=CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCOc1cc(=O)[nH]c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-4-hydroxyquinolin-2(1H)-one (800 mg, 4.09 mmol) and N,N-diisopropylethylamine (1415 μl, 8.18 mmol) in dimethylformamide (13.6 ml) was added 4-bromo-1-butene (415 μl, 4.09 mmol). The solution was heated to 60° C. and stirred for 18 hours. The reaction mixture was purified by column chromatography to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][C@H:7]1[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])=[O:5])C.[Li+].[OH-]>C1COCC1.O.CO>[C:14]1([S:11]([C@@H:9]2[CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:7]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[CH2:8]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1

Procedure:
To a solution of (1R,2R,4S)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester (1.35 mmol) in THF (10 ml) was added a solution of LiOH (3.0 mmol) in water (3 ml) and methanol (3 ml) and stirring was continued at 22° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between ethyl acetate and hydrochloric acid (0.1 N). The organic layer was dried and evaporated to give the title compound as a colorless foam. MS: 368.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[CH3:33][C:34]1[NH:35][C:36]([C:39](O)=[O:40])=[CH:37][N:38]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:39]([C:36]5[NH:35][C:34]([CH3:33])=[N:38][CH:37]=5)=[O:40])[S:3][C:4]=4[N:5]=3)[CH:13]=2)=[O:32])[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: Cc1ncc(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1ncc(C(=O)Nc2nc3cnc(Nc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C)nc3s2)[nH]1
Temperature: 90 °C
Reaction time: 28 h
Yield: 42.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D25(iii) in pyridine (4 mL) were added 2-methyl-1H-imidazole-5-carboxylic acid (194 mg, 1.35 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (899 mg, 2.36 mmol), and the mixture was stirred at 90° C. for 28 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→92/8), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and ethyl acetate to give the title compound (80 mg, 43%) as colorless crystals.