Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(Cl)cc(Cl)c4C[C@H]3O)c3c2CNCC3)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(Cl)cc(Cl)c3C[C@H]2O)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13e) (0.02 g, 0.047 mmol) in dry tetrahydrofuran at −70° C. was added slowly and portionwise 100 μl of a solution of methanesulfonyl chloride (100 μl in 10 ml dry tetrahydrofuran) and after 5 min triethylamine (21 mg, 0.208 mmol). The mixture was stirred at −70° C. for 15 min and then a second portion of the methanesulfonyl/tetrahydrofuran solution above was added (100 μl). The mixture was stirred at −70° C. for 15 min and then a third portion of the methanesulfonyl/tetrahydrofuran solution above was added (50 μl). The mixture was stirred at −70° C. for 3 min, quenched with aqueous NaHCO3 and extracted 3 times with CH2Cl2. The combined organic layers were evaporated to dryness and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 15 mg of 3-[1-((1R,2R)-4,6-Dichloro-2-hydroxy-indan-1-yl)-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (23a).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[NH:24]1[CH2:29][CH2:28][CH2:27][N:26]=[CH:25]1>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:26]2[CH2:27][CH2:28][CH2:29][N:24]=[CH:25]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2)=[O:9]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Reactant: C1=NCCCN1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2C=NCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 8 from 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b,) and 1,4,5,6-tetrahydro-pyrimidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21](O)=[O:22])=[CH:20][N:15]2[CH:14]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:21]([C:19]3[N:18]=[C:16]4[N:15]([CH:20]=3)[CH:14]=[C:13]([Br:12])[S:17]4)=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C(NCc1ccc2c(c1)OCO2)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using benzo[d][1,3]dioxol-5-ylmethanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (46.6 mg, 35%).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)[C:11]([Cl:34])=[CH:10][N:9]=1.O>CC(O)C>[Cl:34][C:11]1[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:19][CH:20]=2)=[N:13][C:8]([O:4][CH:2]([CH3:3])[CH3:1])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(Cl)c(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of potassium tert.-butoxide (116 mg, 1.03 mmol) in propan-2-ol (2 mL) was added (S)-tert-butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (110 mg, 0.26 mmol) and the mixture was shaken at 90° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel, 5 to 15% ethyl acetate in heptan, 10 g ISCO column). White foam (58 mg, 50%). MS (ISP): 449.3 ([{35Cl}M+H]+), 451.1 ([{37Cl}M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[NH2:23]>CS(C)=O>[C:24]([CH:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][CH:29]=[C:18]([O:17][CH3:16])[CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1cccc(CC(N)C(=O)O)c1
Solvent: CS(C)=O
Product: COc1cccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-methoxy-DL-phenylalanine in DMSO to provide the title compound in good yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:23])=[O:4].O[Li].O>O1CCOCC1>[Cl:23][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=3)=[N:11][O:12][C:13]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: CCc1ccc(Nc2noc3c(C(=O)OC)c(Cl)ccc23)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(Nc2noc3c(C(=O)O)c(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl-6-chloro-3-(4-ethylphenylamino)benzo[d]isoxazole-7-carboxylate (211 mg, 638 μmol) in dioxane (10.5 ml) was added a 1N aqueous solution of LiOH hydrate (134 mg, 3190 μmol) and the resulting mixture was heated to 50° C. After 1 hr, the solvent was removed in vacuo, the residue was diluted with H2O and acidified to pH2 with 2N HCl. After diluting with EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated to obtain the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH:15]1[CH:16]=[CH:17][C:18]2S(=O)(=O)[O:22][C:21]([C:33]3[CH:34]=[CH:35][C:36](O)=[CH:37][CH:38]=3)([C:26]3[CH:27]=[CH:28][C:29](O)=[CH:30][CH:31]=3)[C:19]=2[CH:20]=1>>[C:1]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:38][CH2:37][CH2:36]/[CH:35]=[CH:34]\[CH2:33]/[CH:21]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[C:21]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])(=[O:22])[C:19]1[CH:20]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S1(=O)OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)CCCCCCCCCCO
Product: CC(C)CCCCCCCCCCOC(=O)c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCC(C)C

Procedure:
The sebocyte assay procedure described in Example 2 was repeated with additional branched esters. The results that were obtained are summarized in Table 4. Isotridecyl linoleate and isotridecyl benzoate were synthesised according to the procedure of Example 1, using Exxal® 13 isotridecanol as starting material. The results that were obtained are summarized in Table 5. Phenol Red was used as a positive control.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
Compound 175 (200 mg, 0.59 mmol) obtained in Reference Example 114 was dissolved in 4 ml of dimethylformamide. To the solution were added 163 mg (1.18 mmol) of potassium carbonate and 0.56 ml (1.18 mmol) of 1,4-dibromobutane, and the mixture was stirred at 50° C. for 4 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from hexane/ethyl acetate to give 170 mg (yield 61%) of Compound 177 as pale yellow grains.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CN(C=O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Piperazine (12.9 g) was dissolved in DMF (100 mL), and a solution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was added dropwise. The mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to give 1-(2-nitrophenyl)piperazine (7.7 g) as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19](Br)[C:18]([O:22][CH2:23][C@H:24]5[CH2:28][O:27]C(C)(C)[O:25]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33].C(OCC)(=O)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19]([C:32]#[N:33])[C:18]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1(C)c2cc(OC[C@H](O)CO)c(C#N)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Temperature: 220 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-2, 17 mg, 37 mmol) was dissolved in DMA, added with CuCN (17 mg, 5 eq.), and stirred at 220° C. for 2 hr under irradiation with microwave. After cooling, the reaction solution was added with ethyl acetate, and the precipitated solid was filtered to remove the solvent. The resulting residues were purified by HPLC to obtain the title compound (4 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC.[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.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:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:14])=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1CCO)COC2=O
Temperature: 105 °C

Procedure:
A mixture of 5-bromo-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (0.460 g, 1.78 mmol), tributyl(vinyl)tin (0.676 g, 2.13 mmol), LiCl (0.224 g, 5.33 mmol) and Pd (PPh3)4 (0.10 g, 0.087 mmol) in toluene (50 mL) was heated at 100-110° C. under N2 overnight; TLC indicated that reaction had gone to completion and to the solution was poured EtOAc (100 mL) and washed with brine, water, dried over Na2SO4, filtered and concentrated to dryness. The residue was then absorbed into silica gel and separated over silica column to give 5-ethenyl-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.00-7.07 (m, 1H), 5.79-5.84 (m, 1H), 5.50-5.53 (m, 1H), 5.35 (s, 2H), 3.86 (t, J=6.3 Hz, 2H) 2.93 (t, J=6.3 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#N)=[CH:3][N:2]=1.[NH2:9][OH:10].[NH3:11]>>[OH:10][N:9]=[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)[NH2:11]
Reactant: N
Reactant: N#Cc1ccnnc1
Reactant: NO
Product: NC(=NO)c1ccnnc1

Procedure:
The title compound was prepared according to the procedure of Example 79C using the product of Example 83C and hydroxylamine (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 6.19 (s, 2 H), 7.87 (dd, J=5.4, 2.4 Hz, 1 H), 9.25 (dd, J=5.4, 1.4 Hz, 1 H), 9.46 (dd, J=2.4, 1.4 Hz, 1 H), 10.36 (s, 1 H) ppm; MS (DCI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:6]=1)C.[Li+].[OH-].O.Cl>CO.C1COCC1>[CH2:19]([N:13]([CH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Br:11])[C:4]([OH:26])=[O:3])[C:14]([CH:16]1[CH2:17][CH2:18]1)=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid ethyl ester (2.03 g, 4.9 mmol) was treated with 1N aqueous LiOH (10 mL) in MeOH (60 mL) and THF (10 mL). After stirring for 1 hour at room temperature, additional 1N aqueous LiOH (10 mL) was added, and the reaction was stirred for another 2 hours. The mixture was poured into H2O (200 mL) and neutralized with 1N aqueous HCl (50 mL). The solution was extracted three times with EtOAc to give 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:11][CH2:10][C@@H:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: C[C@@H](CO)Nc1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of (2S)-2-[(3-chlorophenyl)amino]propane-1-ol (7.00 g) in N,N-dimethylformamide (19 mL) were added imidazole (2.82 g) and tert-butyl(chloro)dimethylsilane (6.38 g), and the mixture was stirred at 50° C. for 14 hr. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→40%) to give the title compound as a colorless oil (yield: 7.40 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1.[CH3:29][N:30](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[C:29]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:3]=1)#[N:30]
Reactant: Cc1nc(Cl)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(C#N)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Under an atmosphere of nitrogen, combine tert-butyl N-[[4-(6-chloro-2-methyl-pyrimidin-4-y)oxyphenyl]methylsulfonyl]-N-methyl-carbamate (2.24 g, 3.4 mmol), DMF (2 mL), tetrakis(triphenylphosphine)palladium (1.9 g, 1.7 mmol), and zinc cyanide (2.0 g, 16.8 mmol). Heat the mixture to 90° C. and stir for 3 hours. Quench the reaction with water and sodium hydroxide. Extract the mixture with EtOAc; wash the EtOAc extract(s) with brine; dry over magnesium sulfate; filter and concentrate the filtrate under reduced pressure to provide a residue. Purify the title compound via flash column chromatography using 80 g of silica gel, and eluting with a 0-55% gradient of EtOAc in hexanes. Evaporate the relevant fractions to provide the title compound as a yellow oil (1.2 g, 80.9%). MS (m/z): 419 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:3][C:4]=1[C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)#[N:25]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(Cl)cc1-c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cn[nH]c1
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
25.0 mg (0.05 mmol) of 4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 10.5 mg (0.08 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 5.8 mg (10 mol %) of Pd(PPh3)4, 20.7 mg (0.15 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 20 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c(F)c1
Yield: 87.3 %

Procedure:
A solution of 23.9 g(16.9 mL, 0.15mol) of 3,4-difluoronitrobenzene and 29.1 g(39.2 mL, 0.23 mol) of N,N-diisopropylethylamine in 285 mL acetonitrile was treated with 19.3 g(19.7 mL, 0.18 mol) of benzylamine, followed by warming at reflux for 5 h. The mixture was concentrated in vacuo and the residue was dissolved in 200 mL ethyl acetate, followed by extraction with water (3×50 mL). Drying (Na2SO4) and concentration in vacuo afforded a yellow solid, which was recrystallized from hot ethyl acetate-hexane to afford 32.25 g(87%) of the title compound as yellow-orange needles, mp 97.5-99° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>O1CCCC1.CCCCCC>[CH2:11]([O:13][CH2:14][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:12]
Reactant: c1c[nH]cn1
Reactant: CCOCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCn1ccnc1
Temperature: -70 °C
Yield: 56.1 %

Procedure:
Imidazole (20 g) was dissolved in tetrahydrofuran (700 ml) under a nitrogen atmosphere, cooled to −70° C. and n-butyllithium (117.5 ml of a 2.5M solution in hexane) added dropwise, over 15 minutes. The mixture was allowed to warm to −20° C. and stirred at −20° C. for 30 minutes before the dropwise addition of chloromethyl ethyl ether (30.5 g). The mixture was allowed to warm to room temperature and stirred for a further hour. The solvent was removed under reduced pressure to give a residue which was triturated with dichloromethane and filtered through a short pad of Arbacel (trade mark) filter aid. The solvent was removed from the filtrate under reduced pressure to give a mobile oil which was distilled under reduced pressure (0.7 millibars, 0.53 mmHg) to give 1-ethoxymethylimidazole (20.8 g) as an oil.