Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12](OS(C(F)(F)F)(=O)=O)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:26])([CH3:25])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:26])([CH3:25])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(C)(C)c2cc(OS(=O)(=O)C(F)(F)F)c(C)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(C)(C)c2cc(C#C[Si](C)(C)C)c(C)cc21
Yield: 34.5 %

Procedure:
Following General Procedure D in a sealed tube and using 4,4,7-trimethyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 192, 0.86 g, 2.2 mmol), triethyl amine (2 mL), copper(I)iodide (0.083 g, 0.44 mmol), trimethylsilyl acetylene (2 mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.306 g, 0.44 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5% ethyl acetate in hexane as the eluent, and preaprative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase in order to separate recovered starting material from the product, the title compound (0.26 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[N:16][C:17]#[N:18])OC2C=CC=CC=2)[CH:2]=1.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C)C>CO>[C:17]([N:16]=[C:8]([NH:27][C@@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: N#CN=C(Nc1cccnc1)Oc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: C[C@@H](NC(=NC#N)Nc1cccnc1)c1ccccc1
Yield: 7403.7 %

Procedure:
A stirred mixture of N-(3-pyridyl)-N'-cyano-O-phenylisourea (see, Example 5 for procedure) (8.00 g, 0.336 mmol), (R)-α-methylbenzylamine (10.8 mL, 0.0835 mol) and isopropanol (53.3 mL) was refluxed, under nitrogen, for 4 hours. The reaction was complete by TLC with 10% MeOH-1% NH4OH-CHCl3. The mixture was concentrated in vacuo. The residue was mixed with EtOAc several times with concentration after each addition; the resulting solid was triturated with hot EtOAc, collected by filtration and recrystallized from MeOH-CH2Cl2 -EtOAc to give 6.6 g of product: mp 185°-187° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[C:57]([NH2:59])[CH:56]=[N:55]1>CN(C=O)C>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:26]([Cl:25])[C:27]=1[C:28]([NH:59][C:57]1[CH:56]=[N:55][N:54]([CH2:53][C:47]2[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=2[Cl:45])[CH:58]=1)=[O:30]
Reactant: Nc1cnn(Cc2ccc(Cl)cc2Cl)c1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn(Cc2ccc(Cl)cc2Cl)c1)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
A solution of HATU (46 mg, 0.12 mmol) in DMF (200 μl) was added to 2,6-dichlorobenzoic acid (22 mg, 0.11 mmol, Avocado) followed by DIPEA (50 μl, 0.286 mmol) and left to stand for 5 min at ambient temperature. A solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-4-amine (Art Chem GmbH; 53 mg, 0.22 mmol) in DMF (200 μl) was then added and the solution left to stand for 16 h at ambient temperature. The solvent was removed using a Genevac. The sample was dissolved in 1:1 MeOH:DMSO (0.6 ml) and purified by MDAP on a standard C18 column (method D) using acetonitrile-water with a TFA modifier. The solvent was evaporated in vacuo using a Genevac to give the title compound (35 mg); LCMS (System 3): MH+=414, tRET=1.18 min.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH2:36].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:36][CH3:35])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)ccc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)ccc3C)c(=O)n(C)c2n1
Yield: 80 %

Procedure:
Using general method D, Example B30 (150 mg, 0.585 mmol) and Example A44 (165 mg, 0.585 mmol) were combined to give the intermediate sulfide, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (56 mg, 24% yield). Using a procedure analogous to Example A1, the sulfide (56 mg, 0.117 mmol) was combined with 2.0N methylamine in THF (0.59 mL, 1.173 mmol) to afford the desired product, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (43 mg, 80% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.22 (s, 9H), 2.06 (s, 3H), 2.90 (s, 3H), 3.53-3.60 (m, 3H), 6.01 (s, 1H), 7.14-7.16 (d, 1H), 7.27-7.29 (d, 1H), 7.34 (s, 1H), 7.67 (s, 1H), 7.68-7.81 (m, 1H), 8.60-8.65 (m, 1H), 8.74 (s, 1H), 10.06 (s, 1H); MS (ESI) m/z: 461.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)=[O:4]>O.C(O)C>[OH:4][CH2:3][C:5]1[S:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution of sodium borohydride (12.5 g, 330 mmol) in water (150 mL) and ethanol (100 mL) at 0° C. is charged with 5-formyl-thiophene-3-carboxylic acid (20.6 g, 132 mmol) in one portion. After warming to room temperature and stirring for 4 h, the mixture is diluted with water and the resulting precipitate vacuum filtered. The filtrate is concentrated and the resulting aqueous solution is washed with ether (2×). The aq layer is acidified with concentrated HCl and extracted with ether (3×). The combined ether extracts are dried over Na2SO4, filtered and concentrated in vacuo to give 5-hydroxymethyl-thiophene-3-carboxylic acid (14.6, 70%) as a white solid; mp 149° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.60 (s, 1 H), 8.10 (s, 1 H), 7.20 (s, 1 H), 5.52 (t, J=6.0 Hz, 1 H), 4.60 (s, 2 H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:6][CH2:7][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:3][O:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCO
Reactant: ClCCN(CCCl)CCCl
Agent: Cl
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
51.6 g (namely, 0.215 mol) of tris-(2-chloroethyl)-amine hydrochloride were added to the above mixture. The mixture was subsequently heated at the reflux temperature of the 2-methoxyethanol (125° C.) for 12 hours and the solvent was then distilled under reduced pressure. The excess sodium 2-methoxyethanolate was neutralized by adding 11.6 cm3 of aqueous HCl (10 N). The sodium chloride was filtered off and the solution was distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22]O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-chloro-2'-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-chloro-2'-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]3)=[CH:6][CH:5]=2)[CH3:3])[CH2:27][CH2:26]1
Reactant: CC(=O)NC1(c2ccc(C(C)Cl)cc2)CC1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: CC(=O)NC1(c2ccc(C(C)N3CCN(c4ncccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyrimidyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:21]=[CH:20][N:19]=2)=[CH:12][C:11]=1[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:33][C:32]([CH3:35])([CH3:34])[CH2:31][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)CCc1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cc(CCC(=O)O)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
To a solution of ethyl 3-(2-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)pyridin-4-yl)propanoate (72 mg) in THF (1.5 mL) and methanol (0.75 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was neutralized with 1N hydrochloric acid (1.5 mL), and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (50 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccnc(Cl)c1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1

Procedure:
Following a similar procedure to that described in reference example 19, but starting from 2-chloro-4-methylpyridine and ethyl 4-fluorobenzoate, the title compound was obtained.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Product: C[C@@H](NC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) by reacting 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester with D-alanine. MS-(−)-ion: M−1=367.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:21])[O:13][C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]1([C@H:14]2[C@@H:7]3[CH2:6][CH2:5][C:4]4[C:9]([N:8]3[C:12](=[O:21])[O:13]2)=[CH:10][CH:11]=[C:2]([O:1][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:3]=4)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)CCCBr
Reactant: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(O)ccc3N12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(OCCCC(F)(F)F)ccc3N12
Temperature: 90 °C
Yield: 66.7 %

Procedure:
To a solution of 0.65 g (2.3 mmol) of cis-(±)-7-hydroxy-3-phenyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.66 g (3.5 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.64 g (4.6 mmol) of potassium carbonate. The mixture is heated for 4 hours at 90° C. and is then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.60 g of product is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21](I)=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21]([C:28]4[C:29]([O:36][CH3:37])=[CH:30][C:31]([CH2:33][O:34][CH3:35])=[CH:32][C:27]=4[O:26][CH3:25])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: CSc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CCOCC4)CC4CC4)c(SC)nn23)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine (50 mg) dissolved in a mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (50 mg), tetrakis(triphenylphosphine)palladium(0) (40 mg) and barium hydroxide octahydrate (56 mg), and the reaction mixture was heated and stirred for 3 hours at 80° C. Water and ethyl acetate were added to the obtained reaction mixture, insoluble residue was filtered out with celite, and the filtrate was extracted with ethyl acetate. The organic extracts were combined and washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and then by column chromatography using NH Silica (Fuji Silysia) to afford the title compound (36 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O.Cl.[C:26]([O:30][NH2:31])([CH3:29])([CH3:28])[CH3:27].Cl>N1C=CC=CC=1>[C:26]([O:30][N:31]=[CH:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:14]([Cl:24])=[CH:15][C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])=[CH:17][C:2]=1[Cl:1])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
To a mixture of 0.42 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde and 10 ml of pyridine was added 0.13 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.45 g (yield, 92%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde O-tert-butyloxime, nD25.2 1.5185.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CN(C=O)C>[Cl:12][C:13]1[N:21]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)[C:19]([F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(Cl)c(C(=O)O)cc2F)CC1
Temperature: 80 °C

Procedure:
Ethyl isonipecotate was added to a DMF solution of 2,6-dichloro-5-fluoronicotinic acid, and the mixture was stirred at 80° C. to obtain 2-chloro-6-[4-(ethoxycarbonyl)piperidin-1-yl]-5-fluoronicotinic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Br:22])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Solvent: CC#N
Product: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Br)cc21
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A solution of N-trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.710 g, 2.36 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.504 g, 2.83 mmol), and stirred overnight at 20 C. The product mixture was concentrated, diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.561 g of a clear oil. MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[S:15])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Br:14])(=O)[CH3:2].Cl>C(=O)([O-])O.[Na+]>[Br:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]1[C:1]([CH3:2])=[N:4][N:5]=[C:6]1[SH:15]
Reactant: CC(=O)NNC(=S)Nc1ccncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nnc(S)n1-c1ccncc1Br
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide (200 mg, 0.6917 mmol) was dissolved in sodium hydrogen carbonate (4 mL,) and stirred at 50° C. for 2 hrs and at 100° C. for 5 hrs. The reaction mixture was then allowed to stand at RT for 48 h before it was carefully neutralised with dilute HCl and partitioned with 10% MeOH in DCM. The aqueous layer was extracted with further 10% MeOH in DCM (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(3-bromopyridin-4-yl)-5-methyl-4H-1,2,4-triazole-3-thiol as an orange solid (152.6 mg). MS (ES+) 272.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1F
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3F)cc2)cc1

Procedure:
Prepared as described in Example 36, Step 6 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester and 2-(4-bromo-phenyl)-2-methyl-propionic acid ethyl ester; purification by preparative HPLC was utilized.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: COC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccc5)c(C)c4)c23)CC1
Yield: 37 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and 4-methoxypiperidine (prepared as described in Example 118, starting material) to give the title compound in 37% yield; NMR Spectrum: 1.37-1.43 (m, 2H), 1.78-1.81 (m, 2H), 2.18-2.22 (m, 2H), 2.22 (s, 3H), 2.75-2.78 (m, 4H), 3.12-3.16 (m, 1H), 3.20 (s, 3H), 4.40 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.23 (s, 1H), 8.32 (s, 1H); Mass Spectrum: 489 (MH+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl-].[NH4+:35]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:32])([CH3:33])[C:29]([NH2:35])=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(=O)O)c3)ccc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C(C)(C)C(N)=O)c3)ccc1-2

Procedure:
Following the procedure for 240, 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid was reacted with ammonium chloride to give 439. MS (ESI+) 464.1. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.50 (dd, J=8.3, 1.8, 1H), 7.39 (d, J=1.7, 1H), 7.17 (br, 1H), 6.79 (br, 1H), 5.93-5.74 (m, 1H), 4.39 (t, J=5.0, 2H), 3.45 (t, J=5.0, 2H), 1.75 (s, 6H), 1.56 (d, J=6.6, 6H)