Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CN(C)Cc1ccc(CCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>ClCCl>[Br:37][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 2-(4-Phenoxy-phenoxy)-ethanol (2.2 g, 9.55 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and dichloromethane (DCM) (36.7 mL) after stirring at 0° C., was added N-Bromosuccinimide (1.87 g, 10.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. Reaction mixture was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.5 g, 89%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [N:1]1[CH:5]([CH:6]2[CH2:11][O:10][CH2:9][CH2:8][N:7]2C(OC(C)(C)C)=O)[N:4]=[N:3][N:2]=1.[ClH:19]>CCOC(C)=O>[ClH:19].[N:4]1[CH:5]([CH:6]2[CH2:11][O:10][CH2:9][CH2:8][NH:7]2)[N:1]=[N:2][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C1N=NN=N1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1COCC(C2N=NN=N2)N1
Yield: 70 %

Procedure:
Tert-butyl 3-(5H-tetrazol-5-yl)morpholine-4-carboxylate (2 g, 7.8 mmol) was reacted with a solution of HCl in EtOAc (6 mol/L, 30 mL) according to the procedure as described in Example 18, Step B to give the title compound as a grey solid (1.05 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].C(=O)([O-])[O-].[K+:37].[K+]>CO.O>[K+:37].[C:23]([NH:22][C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)NC(C)(C)C)c(OC)c1

Procedure:
(4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Example No. 22, 28a, 6.27 g, 14.2 mM) is stirred at room temperature under nitrogen in methanol (50 mL). To this is added a solution of potassium carbonate (2.50 g, 18.1 mM) in water (6 mL). After 6 hours the reaction is evaporated under reduced pressure to remove the methanol and the residue freeze dried. There is obtained a quantitative yield of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (29a) admixed with potassium carbonate salts as a powder.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10]N=[C:8]2[Cl:15])=[O:4].[CH3:16]C(C[AlH]CC(C)C)C>C1COCC1>[Cl:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=2)[N:11]=[CH:10][CH:16]=1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1ccc2ncnc(Cl)c2c1
Solvent: C1CCOC1
Product: OCc1ccc2nccc(Cl)c2c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of methyl-4-chloroquinazoline-6-carboxylate (3.5 g, 0015 mol) in dry THF (35 mL) at −25° C. was added DIBAL-H (4.4 g, 0.031 mol) and stirred at −25° C. to RT for 2 h. The reaction mixture was cooled to −10° C. and quenched with 10% aqueous NaHCO3 (9 mL). The reaction mixture was extracted with ethylacetate (100 mL), washed with water, brine and dried. The solvent was removed under vacuum to give 4-chloroquinoline-6-yl methanol (2 g, 66%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH2:40])=[CH:29][CH:28]=2)[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH:40][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[CH:31][CH:32]=2)[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 50 %

Procedure:
Following the procedure of Example 51, 5-n-butyl-2,4-dihydro-2-[5-(propionylamino)-2-(trifluoromethyl)phenyl]-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step F) was reacted with 2-chlorobenzoic acid (3 equivalents), CDI (3 equiv), and DBU (3 equiv). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) afforded a 50% yield of the title compound as a solid, mp 102°-105° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 740 (M+1)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: C1COC(CN2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CCCO2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 23%. White crystals, m.p. 98–100° C.; IR (KBr): ν 1731 (C═O) cm−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1>O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Agent: O=[Mn]=O
Product: O=Cc1cncc(Br)c1
Yield: 51.1 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (1.13 g, 6.00 mmol) was dissolved in CHCI3 (40 mL) and treated with MnO2 (3.60 g). The reaction mixture was heated at reflux temperature for 3 h. The hot reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to yield the title compound (0.570 g, 51%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([CH3:33])=[CH2:32])[CH:28]=[C:27]([Cl:34])[C:26]=1[Cl:35].Cl>CN(C=O)C.CC(=O)OCC.O>[CH3:14][C:4]1([CH3:15])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:32][C:31]([CH3:33])([C:29]4[CH:28]=[C:27]([Cl:34])[C:26]([Cl:35])=[C:25]([Cl:24])[CH:30]=4)[O:13][N:12]=3)=[CH:10][C:5]1=2
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Reactant: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(O)c2ccc(C3=NOC(C)(c4cc(Cl)c(Cl)c(Cl)c4)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 37.4 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (500 mg, 2.44 mmol) in DMF (10 mL) at rt was added NCS (392 mg, 2.93 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (277 mg, 1.26 mmol) and TEA (140.4 mg, 1.39 mmol) in DMF (15 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at this temperature for 1 h and then at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2 and then poured into water followed by extraction with EA (100 ml×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (2:1) to give the final title compound (200 mg, yield 37.5%) as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.73-7.62 (m, 5H), 3.79-3.63 (q, 2H), 1.75 (s, 3 H), 1.46 (s, 6H). MS: m/z=424 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([Cl:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 3-acetamido-6-chlorobenzotrifluoride (908 mg, 3.82 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature 3 h, and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 990 mg (91%) of crude 3-acetamido-6-chloro-4-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 770 mg of pure compound as yellow needles. 1H NMR (CDCl3): δ 2.326 (S, 3H), 8.345 (s, 1H), 9.293 (s, 1H), 10.222 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C(OCC)(=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCc3ccccn3)ccc2s1
Yield: 84 %

Procedure:
To a solution of 77 mg (0.20 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 3 ml ethyl acetate was added 200 mg potassium carbonate and 56 mg (0.22 mmol) 2-(bromomethyl)pyridine, hydrobromide. The reaction mixture was heated at reflux for 10 h and poured into brine. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethyl acetate 3:2) to yield (2-{[5-(Pyridin-2-ylmethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (52) (80 mg, 0.168 mmol) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:17][C:13]=2[C:12]([CH3:42])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:17][C:13]=2[C:12]([CH3:42])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:22]Br.O>ClCCl>[Br:22][C:12]1[C:11]([CH3:14])=[CH:10][C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:13]=1
Reactant: CCCCCCOc1ccc(C)cc1OCCCCCC
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1cc(C)c(Br)cc1OCCCCCC
Yield: 90.3 %

Procedure:
Next, 91 g (0.31 mol) of the 1,2-di(n-hexyloxy)-4-methylbenzene was dissolved in 270 g of dichloromethane. While cooling in an ice/water bath, 49.7 g (0.31 mol) of bromine was added dropwise at a temperature below 10° C. After the completion of dropwise addition, 200 g of water was added. The organic layer was separated and washed with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was concentrated on a rotary evaporator, yielding 120 g of an oily matter. This was distilled in vacuum (boiling point 180–190° C./0.5 Torr), obtaining 104 g (yield 90%) of 5-bromo-1,2-di(n-hexyloxy)-4-methylbenzene.
Reaction SMILES: [CH2:1]([N:8]([C@H:13]([CH3:16])[CH2:14][OH:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[H-].[Na+]>[CH2:1]([N:8]1[C@H:13]([CH3:16])[CH2:14][O:15][CH2:10][C:9]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)N(Cc1ccccc1)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1COCC(=O)N1Cc1ccccc1

Procedure:
(R)-N-Benzyl-2-chloro-N-(1-hydroxypropan-2-yl)acetamide (9.49 g, 39.3 mmol) was dissolved in THF (78.5 mL) before NaH—60% in oil (1.73 g, 43.2 mmol) was added and the mixture stirred at reflux for 4 h. The reaction was quenched with a few drops of water, concentrated, diluted with dichloromethane, filtered, and concentrated to give the title compound. MS (ES+): 206(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]1[N:14]=[C:15]3[C:21]([CH:22]=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3=[N:17][CH:18]=1)=[N:5][N:6]2[CH3:12].S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:13]1[N:14]=[C:15]3[C:21]([C:22]([OH:34])=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3=[N:17][CH:18]=1)=[N:5][N:6]2[CH3:12]
Reactant: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(F)cc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (226 mg, 0.51 mmol) in 1,4-dioxane (15 ml) and water (3 ml) at 0° C. was added sulfamic acid (297 mg, 3.06 mmol). Then a solution of sodium chlorite (80%, 75 mg, 0.66 mmol) and potassium dihydrogen phosphate (834 mg, 6.13 mmol) in water (12 ml) was added via dropping funnel over ˜15 min. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine then dried over MgSO4 and concentrated to afford 230 mg (98%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1)=[O:38]
Reactant: O=C(O)c1cccc(F)c1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccc(F)c6)nn(C)c5c4)ccnc3NC2=O)cc1
Temperature: 100 °C
Yield: 13.4 %

Procedure:
A solution of 5-[(3-amino-1-methyl-1H-indazol-6-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.23 mmol; 1.00 eq.),3-fluorobenzoic acid (35.80 mg; 0.26 mmol; 1.10 eq.), pybop (157.16 mg; 0.30 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (115.48 μl; 0.70 mmol; 3.00 eq.) was stirred at room temperature for 22 hr. Additional pybop was added and the reaction was heated to 100 degrees C. but the reaction did not go to completion. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 17 mg (26%) of 3-fluoro-N-(6-{[3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]oxy}-1-methyl-1H-indazol-3-yl)benzamide as a yellow solid. LC-MS (M+H=553, obsd.=553).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[CH:15]([OH:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.C(N(CC)CC)C.S(=O)(=O)=O.[NH+]1C=CC=CC=1>CS(C)=O.O>[CH3:1][C:2]1([CH3:27])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:3]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(O)CCCCc2ccccc2)c1
Agent: O=S(=O)=O
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)CCCCc2ccccc2)c1
Reaction time: 6 h
Yield: 59.6 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-5-phenyl-pentan-1-ol (0.62 g, 1.7 mmoles), prepared as described in example 17, in DMSO (10 ml) was added with triethylamine (35 ml) and, after 30 minutes, with pyridinium sulfur trioxide (1.62 g, 10.2 mmoles). After 6 hours, the mixture was diluted with 10 volumes of water and twice extracted with ethyl ether. The organic phases were washed with water, discoloured with charcoal, anhydrified and concentrated. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 7:3) to give 0.37 g of the title compound (yield: 60%).
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([C:2]2([OH:1])[CH2:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(C2(O)CCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C2(O)CCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A 250 mL flask was charged with 4.1 g (23.5 mmol) 4-(1-hydroxy-cyclobutyl)-benzonitrile and 100 mL anhydrous THF then cooled to 0° C. Next, 70.5 mL (70.5 mmol) 1M LiAlH4 was added dropwise. The reaction mixture was stirred at 0° C. for 10 minutes then heated to reflux for 30 minutes, then cooled to 0° C. and quenched with MeOH. Diluted with methylene chloride and washed with water (2×100 mL). The organic was filtered through Celite and concentrated to give 2 g of a yellow solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[C:14]([Cl:35])=[CH:15][C:16](F)=[C:17]([S:19]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:18]=1>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:16]1[CH:15]=[C:14]([Cl:35])[C:13]([Br:12])=[CH:18][C:17]=1[S:19]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:1]([O:8][CH3:9])=[O:7]
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(Cl)c(Br)cc1S(=O)(=O)N1CCC(C)(C)c2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a dry DMF (10 mL) solution containing dimethyl malonate (0.79 mL, 6.9 mmol), was added NaH (276 mg, 6.9 mmol) slowly at 0° C. under N2. The slurry was stirred for 10 min, then 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (1.0 g, 2.3 mmol) in dry DMF (5 mL) was added dropwise. The mixture was heated at 80° C. for 24 hrs, cooled to rt, carefully quenched with 1N HCl (10 mL), and extracted with ethyl acetate. The organic layer was washed with saturated aq. NaHCO3 solution and water, then was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with hexane/ethyl acetate (100/15) to yield 2-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-malonic acid dimethyl ester (0.75 g). MS: 545.9 (M+H); tR=2.64 min (method 1)