Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCn1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 100 %

Procedure:
Benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 1.3 mmol) was stirred in methanol (9.5 mL) with Pd/C (70 mg, 0.070 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (350 mg, 99%). ESI-MS m/z calc. 269.2, found 270.5 (M+1)+; Retention time: 0.80 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([C:26]4[O:25][CH:29]=[CH:28][N:27]=4)=[CH:36][CH:35]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2ncco2)cc1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2ncco2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of 4-(1,3-oxazol-2-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 1-10% mixtures). Yield: 89 mg (63% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:26]1[CH:27]=[N:28][C:29]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:42])[CH:39]=3)[C:34]([S:49][CH3:50])=[CH:33]2)=[N:30][CH:31]=1.[CH3:51][N:52]1[CH:56]=[C:55](B(O)O)[CH:54]=[N:53]1>C1COCC1.O.C(OCC)(=O)C.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]>[CH3:51][N:52]1[CH:56]=[C:55]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:41]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[O:42])[CH:39]=4)[C:34]([S:49][CH3:50])=[CH:33]3)=[N:30][CH:31]=2)[CH:54]=[N:53]1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Cn1cc(B(O)O)cn1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1cn(-c2ncc(-c3cnn(C)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 30 °C

Procedure:
Potassium carbonate (254 mg, 1.846 mmol, 2.0 eq), Pd2(dba)3 (84 mg, 0.0923 mmol, 0.1 eq) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol, 0.05 eq) were added to a solution of (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (400 mg, 0.923 mmol, 1.0 eq) and (1-methyl-1H-pyrazol-4-yl)boronic acid (140 mg, 1.108 mmol, 1.2 eq) in THF/water (20 mL, 4:1) stirred under an argon atmosphere at 30° C. The reaction mixture was stirred at the same temperature for 2 h and the cooled to ambient temperature and diluted with ethyl acetate (10 mL). The mixture was filtered through a pad of celite, washed with water, dried over sodium sulfate and evaporated. The residue was purified by column chromatography [100-200 mesh, 2% methanol in dichloromethane]. White solid. Yield: 380 mg (95% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(C2=NCCC2)cc1
Yield: 80.3 %

Procedure:
tert-Butyl 4-(4-bromophenyl)-4-oxobutylcarbamate (3.42 g, 10 mmol) was stirred in TFA (10 mL) for 6 hrs. Then 50% NaOH solution was added to the mixture to make pH=13-14, the white precipitate was filtrated, washed with water and dried to give the title compound as a white solid (1.8 g, yield 80%). LC-MS (ESI) m/z: 224 (M+1)+.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.C1(OC2C=CC=CC=2)C=CC=CC=1.[C:36]([O:44]CC)(=O)[CH2:37][C:38]([O:40]CC)=O>>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:38]([OH:40])=[CH:37][C:36](=[O:44])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1cccc([N+](=O)[O-])c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)cc(O)c2c(=O)n(C3CC3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c21
Temperature: 230 °C
Yield: 51 %

Procedure:
To 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 8 (16 g) obtained in Step 4 were added diphenyl ether (160 ml) and diethyl malonate 9 (40 ml), and the mixture was stirred under heating at 230° C. for 11 hrs while evaporating the resulting ethanol. The reaction mixture was purified by column chromatography (chloroform→chloroform:acetone=9:1) to give 3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 10 (10 g, 51%) as a brown foamy oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=4)=[CH:23][C:22]=3[CH3:37])[N:11]=2)=[CH:5][CH:4]=1)#[N:2].C1C=[N:42]C2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl-].[NH4+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([NH2:42])=[O:35])=[CH:32][CH:33]=4)=[CH:23][C:22]=3[CH3:37])[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(-c2ccc(C(N)=O)cc2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ncn2C
Temperature: 80 °C

Procedure:
To a solution of 4′-(2-(4-cyanophenylamino)-9-methyl-9H-purin-6-yloxy)-3′,5′-dimethylbiphenyl-4-carboxylic acid (40 mg, 0.082 mmol), HOAt (23 mg, 0.18 mmol), and EDCI (35 mg, 0.18 mmol) was added ammonium chloride (25 mg, 0.47 mmol) followed by TEA (0.1 mL, 0.72 mmol) at rt. The reaction mixture was heated at 80° C. for 1 h and added H2O. The solid material which precipitated was collected by filtration and purified on silica gel preparative TLC to yield the desired compound. NMR (DMSO-d6): δ 10.10 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 8.03 (d, 2H), 7.87 (d, 2H), 7.66 (s, 2H), 7.62 (d, 2H), 7.43 (s, 1H), 7.35 (d, 2H), 3.80 (s, 3H), 2.18 (s, 6H); MS (ESI): m/z 490 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]=[O:13])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[O:13][C:16]4[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: Cn1cc(C=O)c2ccc(F)cc21
Solvent: CCO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COC(=O)Cc1ccc2nc(-c3cn(C)c4cc(F)ccc34)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
In ethanol (15 ml), 6-fluoro-1-methylindole-3-carbaldehyde (500 mg, 2.82 mmol) and methyl 4-amino-3-hydroxyphenylacetate (767 mg, 4.23 mmol) were stirred at room temperature for 2 hours. Iodobenzene diacetate (1.09 g, 3.38 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was purified chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (1:1, v/v) eluate fractions, methyl (2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate (889 mg, 93%) was obtained as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: CS(=O)(=O)OCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 491 mg (2.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.35 g (2.00 mmol) methanesulfonic acid furan-2-ylmethyl ester and 0.83 g (6.00 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19](O)=[O:20])[CH2:15][C:16](=[O:18])[NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.O.C(OCC)(=O)C>[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
5.00 Grams of H-Leu-OEt.HCl, 5.95 g of Boc-Asn-OH and 4.11 g of HOBT.H2O were suspended in 100 ml of THF. To this suspension was added 4.70 ml of WSC with ice-cooling. The mixture was stirred for 7 hours at room temperature. To the reaction mixture were added 100 ml of ethyl acetate and 200 ml of water to effect extraction. The ethyl acetate layer was washed with 50 ml of a saturated aqueous sodium bicarbonate solution three times, 50 ml of a saturated aqueous sodium chloride solution once, 50 ml of 1N hydrochloric acid three times and 50 ml of a saturated aqueous sodium chloride solution once in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was solidified with isopropyl ether to obtain 7.00 g (yield: 72.9%) of the above objective compound. Melting point: 155°-157° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)NS(C)(=O)=O
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)NS(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-{1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butyl}-methanesulfonamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: COC(=O)[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5]([CH3:7])C.BrC1C=C2C(CN(CCC[C:53]([O:55][CH3:56])=[O:54])C2=O)=CC=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:16][N:8]1[CH2:4][CH2:5][CH2:7][C:53]([O:55][CH3:56])=[O:54]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Reactant: COC(=O)CCCN1Cc2ccc(Br)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)CCCN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 348 was prepared analogous to compound of example 330 by reaction of the compound of example 347, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.[Si]([C:20]([F:23])([F:22])[F:21])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:14]([OH:15])[C:20]([F:23])([F:22])[F:21])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-[1,1′-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (1.2 g, 8.7 mmol) in THF (20 mL) and cooled to 0° C. To this solution was added TBAF (1.46 mL, 1M in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HCl (5 mL) and stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorless oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1>Cl.COCCOC.CCO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[C:10]2[CH:22]=[CH:23][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Nc1ccc(C(=O)c2ccc(F)cc2)cc1
Yield: 83.6 %

Procedure:
A solution of tin (II) chloride dihydrate (1.05 g, 4.7 mmol) in conc hydrochloric acid (4.2 mL) was added to 4-fluoro-4′-nitrobenzophenone (0.37 g, 1.5 mmol) in a mixture of DME (4 mL) and EtOH (5 mL) at such a rate that the internal temperature remained under 35° C. After 5h the reaction mixture was quenched by addition to ice-water (40 mL). The mixture was diluted with DCM (25 mL), made basic (pH=11) by addition of 10% NaOH, and then extracted with DCM (2×25 mL). The combined extracts were washed with water and brine, dried (anhyd Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to afford 4′-amino-4-fluorobenzophenone (0.27 g, 83%) as a white solid. 1H-NMR (DMSO-d6) δ 7.68 (2H, dd, J=5.6, 8.8), 7.51 (2H, d, J=8.8), 7.32 (2H, app t, J=8.8), 6.61 (2H, d, J=8.8), 6.18 (2H, br s). A solution of tin (II) chloride dihydrate (1.05 g, 4.7 mmol) in conc hydrochloric acid (4.2 mL) was added to 4-fluoro-4′-nitrobenzophenone (0.37 g, 1.5 mmol) in a mixture of DME (4
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[F:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1ccccc1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(Cc2ccccc2F)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(2-fluorophenyl)methyl]pyridazine (Intermediate 55) except that the product was recrystallised from a mixture of ethyl acetate and heptanes.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[F:8][C:9]([F:29])([C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][OH:12].[H-].[Na+]>CN(C)C=O>[F:8][C:9]([F:29])([C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][O:12][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(CBr)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 66 %

Procedure:
In a manner similar to that described above, 12.0 grams of 3-bromomethyl-3-methyloxetane (73 mmol) was reacted with 26.5 grams of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol (72.7 mmol) in 300 milliliters of dimethylformamide in the presence of 3.9 grams of a 50 weight percent dispersion of sodium hydride (81 mmol) in mineral oil at 85° C. for 24 hours to give 21.5 grams (70% yield) of 3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxymethyl)-3-methyloxetane, a colorless oil with a boiling point of 66°-68° C./2-2.5 mm-Hg; 1H NMR (CDCl3) δ 4.50 and 4.36 (AB, J=5.5 Hz, 4H), 3.78 (t, J=6.6 Hz, 2H), 3.53 (s, 2H), 2.42 (triplet of triplets, J=6.6 and 18 Hz, 2H), and 1.31 (s, 3H); 13C NMR (CDCl3) δ 79.89, 78.30, 63.31, 39.9, 31.64 (t), and 21.1 (signals due to carbons bearing fluorines are not included due to the complex splitting patterns and low peak intensities); 19F NMR δ -81.4 (3 F), -113.8 (2 F), -118.2 (2 F), -112.3 (2 F), -124.1 (2 F) and -126.7 (2 F). The elemental analysis was: Calculated for C13H13F13O2 : C, 34.8; H, 2.9; F, 55.1. Found: C, 35.1; H, 3.0; F, 54.7.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(cnn2-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Reaction time: 15 h
Yield: 45.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 44.5 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL). After 15 h, the mixture was concentrated in vacuo and 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% of a methanol containing 10% ammonium hydroxide solution in dichloromethane) gave 2-(5-methoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (7.4 mg, 46%). MS (M+H)+=365; 1H NMR (DMSO-d6) d: 9.04 (s, 1H), 8.70 (dd, J=9.3, 4.6 Hz, 1H), 8.52 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 7.76 (dd, J=8.9, 2.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 3.86 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.IC1C=CC=CC=1.C(O)(=O)C.C(O)(=O)C.C(OCC)C>ClCCl>[CH:2]([CH2:3][C:4]1([CH2:10][CH2:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:1]
Reactant: CCOC(=O)C(CCC1(CCO)CCCCC1)(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CCOC(=O)C(CCC1(CC=O)CCCCC1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of triethyl 3-[1-(2-hydroxyethyl)cyclohexyl]-1,1,1-propanetricarboxylate (230 mg) in dichloromethane (6 mL) were added diacetic acid iodobenzene (213 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (9.3 mg) at room temperature. The solution was stirred at room temperature for 16 hours. Diethyl ether was added to the solution, and it washed in turn with an aqueous sodium thiosulfate solution, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure to give the title compound. This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30]C3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1CC(NN)=O.O1CCC(CC(NN)=O)C1>>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:37]3[CH2:38][CH2:39][CH2:40][O:36]3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: NNC(=O)CC1CCCO1
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CC3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-(tetrahydrofuran-2-yl)acetohydrazide (compound 138.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 470 (M+H)+.