Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].O>C1COCC1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][C:6]=1[O:8][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(Br)cc1O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([Si](C)(C)C)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of 5-bromo-2-methylphenol (Intermediate 1, 3.6 g, 19.3 mmol) in THF (150 mL) at −78° C. was added n-butyl lithium (30 mL, 1.6 M solution in hexanes, 48.1 mmol) and the reaction stirred at this temperature for 30 minutes. Trimethylsilyl chloride (6.1 mL, 48.1 mmol) was then added and the solution stirred at −78° C. for 1.5 hours. The reaction was allowed to warm to room temperature and water (75 mL) was added. The mixture was extracted with diethyl ether (2×75 mL) and the combined organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to afford 2-methyl-5-(trimethylsilyl)phenoxytrimethylsilane (5 g) as a yellow oil. 1H NMR δH 0.26 (9 H, s), 0.29 (9 H, s), 2.20 (3 H, s), 6.93 (1 H, d, J=1.1 Hz), 7.04 (1 H, dd, J=7.3, 1.1 Hz), 7.16 (1 H, d, J=7.4 Hz).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[CH:27]=[CH:28][C:29](O)=[O:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:29]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:30])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=C(O)C=Cc1ccc(F)c(Cl)c1
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-4-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum MS (ISP)=464.3 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; mp. 195.1° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:18]=3)[C@@:13]3([CH2:32][O:31][C:30]([NH2:33])=[N:29]3)[C:12]=2[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.Br[C:44]1[N:45]=[N:46][C:47]([CH3:50])=[CH:48][CH:49]=1>CN(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>[F:7][C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:17][CH:18]=3)[C@@:13]3([CH2:32][O:31][C:30]([NH2:33])=[N:29]3)[C:12]=2[CH:11]=[C:10]([C:44]2[N:45]=[N:46][C:47]([CH3:50])=[CH:48][CH:49]=2)[CH:9]=1
Reactant: Cc1ccc(Br)nn1
Reactant: CC1(C)OB(c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)OC1(C)C
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: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)nn1
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated, 1 mL), Pd(PPh3)4 (23.52 mg, 0.020 mmol), (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (200 mg, 0.407 mmol), and 3-bromo-6-methylpyridazine (141 mg, 0.814 mmol) were combined in DMF (5 mL). The solution was heated at 85° C. overnight. The solution was filtered through celite and the derived residue was purified via Gilson HPLC (gradient elution 25-65% MeCN/H2O, 0.1% TFA) to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(6-methylpyridazin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. MS m/z=458.0 [M+H].
Reaction SMILES: [CH:1]([OH:3])=[O:2].F[C:5]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:18]([C:35]([F:38])([F:37])[F:36])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].NC1C=CC(C(N)=O)=CC=1[F:49]>C(O)=O>[CH:1]([OH:3])=[O:2].[F:49][C:13]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=2)[C:18]([C:35]([F:36])([F:38])[F:37])=[CH:17][N:16]=1)[C:7]([NH2:9])=[O:8]
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)c(F)c2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: NC(=O)c1ccc(N)c(F)c1
Solvent: O=CO
Product: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)cc2F)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
Compound 14 was prepared in a manner similar to that described Example 13 for the preparation of 13 except that 4-amino-3-fluorobenzamide (1.5 equ/189 μM) was used instead of 4-amino-2-fluorobenzamide to provide the formic acid salt of 14 as a cream colored solid. Yield: 26 mg, 37%. LC-MS M+1=514. NMR (d6-DMSO) : 2.98 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.19 (1H, s). FAK IC50: <0.000595 μM (Table 1, Example 322)
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9][C:10]1[C:11]2[NH:27][CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([S:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:28])[C:11]=2[NH:27][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c(Br)c[nH]c23)c(C)c1
Yield: 23 %

Procedure:
To a solution of 4-(4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (22.7 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added NBS (10.5 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by reversed phase HPLC to give the product as a white solid (6.4 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, Raney Nickel (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 30-40 psi of hydrogen pressure for a period of 8-10 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100-105 g, 80-83%).
Reaction SMILES: Cl.ClC[C:4]1[C:9]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[CH:5]=1>>[C:13]([NH:12][CH2:11][CH2:10][C:9]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=1)(=[O:15])[CH3:14]
Reactant: COc1cc(CCl)c(CCNC(C)=O)cc1OC
Agent: Cl
Product: COc1ccc(CCNC(C)=O)cc1OC

Procedure:
A sample of this material was recrystallized from ethyl acetate and obtained as clusters of sword-shaped crystals, m.p. 151°-153° dec with evolution of HCl. This substance is the hydrochloride of N-(6-chloromethyl-3,4-dimethoxyphenethyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (113 mg, 0.29 mmol) was dissolved in absolute CH2Cl2 (14 ml) and acetyl chloride (27 mg, 0.34 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=15 cm, V=5 ml). A yellowish resin was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C>CCCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@@H:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1CC2(CCC1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: O=C(N[C@H]1CC2(CC[C@@H]1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1

Procedure:
Benzyl [8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate (528 mg) was resolved by HPLC using a chiral AD column (13% isopropanol in heptane) to give benzyl [(7S,8R)-8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate as the slower eluting enantiomer.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(N(C(C)C)C(C)C)C.Cl.[NH2:47][OH:48].Cl>O1CCOCC1>[OH:48][NH:47][C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:35][CH3:36])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:18])[N:14]=2)[CH:6]=[CH:5][N:4]=1)=[NH:2]
Reactant: NO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=N)NO)c2)nc1OC

Procedure:
A suspension of 100 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, in dioxane (10 ml) was treated at RT with 0.17 ml of N-etyldiisopropylamine then with 69 mg of hydroxylamine hydrochloride and refluxed 12 h until the reaction was complete according to TLC analysis. The mixture was poured into cold diluted HCl and the product extracted into AcOEt. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The solid residue was crystallised from CH2Cl2/Et2O to afford N-hydroxy-4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxamidine as off-white crystals. ISN mass spectrum, m/e 536.2 (M−1 calculated for C24H23N7O6S: 536).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18](Cl)=[O:19])[CH:14]=1>C(Cl)Cl>[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[O:19])[CH:14]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (342 mg, 2.0 mmol) and TEA (1.39 mL, 10 mmol), was added 5-methylisoxazole-3-carbonyl chloride (300 mg, 2.06 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 16 hr, and triturated with aqueous sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and evaporated. The residue on filtered through a silica plug to give the title compound as a cream colored solid (330 mg, 57%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[CH3:13][C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:14]1([CH3:16])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: CC(C)=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 1.5 h

Procedure:
A solution of tryptophol (8 g, 0.05M), acetone (5 g) and p-toluenesulfonic acid (100 mg) in 100 ml benzene containing hydrated alkali-aluminum silicate (Molecular Sieves No. 4) is heated to reflux for 1 hr. More p-toluenesulfonic acid (100 mg) and the ketone, acetone (3 g), is added and the reflux contained for a further 1.5 hr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)O)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1Br)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
3-(3-Bromo-4-methoxyphenyl)propionic acid (5.0 g, 19.3 mmol) and thionyl chloride (10 ml) were refluxed for 1 hour. This reaction mixture was concentrated under reduced pressure to remove the excess thionyl chloride and the residue was dissolved in 1,2-dichloroethane (50 ml). To this solution was added aluminum chloride (2.8 g, 20.8 mmol) over 10 minutes on an ice bath and the mixture was further stirred at room temperature for 1 hour. This reaction mixture was poured in iced water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane to provide the title compound (yield 4.3 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=3)[CH:16]=[C:17]([OH:19])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[C:30]([OH:35])(=O)[C:31]([CH3:33])=[CH2:32]>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32])=[CH:22][CH:21]=3)[CH:16]=[C:17]([O:19][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:30](=[O:35])[C:31]([CH3:33])=[CH2:32]
Reactant: OCCCOc1ccc(-c2cc(O)cc(-c3ccc(OCCO)cc3)c2)cc1F
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCCOc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(OCCOC(=O)C(=C)C)cc3)c2)cc1F

Procedure:
In analogy to step 2 of Example 1, 3″-fluoro-4-(2-hydroxy-ethoxy)-4″-(3-hydroxy-propoxy)-[1,1′;3′,1″]terphenyl-5′-ol and methacrylic acid are reacted to give 2-methyl-acrylic acid-3-{3″-fluoro-5′-(2-methyl-acryloyloxy)-4-[2-(2-methyl-acryloyloxy)-ethoxy]-[1,1′;3′,1″]terphenyl-4″-yloxy}-propyl ester as colourless crystals with a m.p. 70° C.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].CO.[C:21]([OH:26])(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[C:21]([O-:26])(=[O:25])[CH:22]([CH3:24])[CH3:23].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)[O-]

Procedure:
Alternatively, a 1 M solution of tetrabutylammonium hydroxide in methanol (1 L, 1 mol) and isobutyric acid (88.5 g, 1 mol) was stirred at ambient temperature for 30 min. The solvent was removed in vacuo to afford the title compound (5) as a waxy solid, which was used without further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Trichloroacetyl isocyanate (470 μL, 4.0 mmol) was added dropwise to a solution of 2-amino-5-(2-naphthyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 1.0 g, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL) at −30° C. over 5 minutes, and the whole was stirred for 1.5 hours. Furthermore, 2.0 M ammonia solution in methanol (20 mL, 40 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. The precipitated solid was filtered off and washed with a mixed solvent of diethylether-ethanol (3:1) (20 mL). The obtained solid was dried at 40° C. under reduced pressure to give the target compound (0.67 g) as a pale gray solid (Yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:37]5[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.98 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:28][NH2:29]>>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:29][NH:28][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc(OC)cc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Product: COc1ccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)cc1
Temperature: 100 °C

Procedure:
To 210 mg of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(4-methoxyphenyl)pyridine was added 3 ml of hydrazine monohydrate, and the mixture was heated at 100° C. in a stream of nitrogen for 30 minutes. After solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, followed by collection of the crystals by filtration.
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH2:3][CH3:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH3:18])=[C:12]([CH2:14][CH:15]=[O:16])[CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH3:18][O:17][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][C:12]=1[CH2:14][CH:15]([OH:16])[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: COc1ccc(F)cc1CC=O
Reactant: CCC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)Cc1cc(F)ccc1OC
Yield: 75.3 %

Procedure:
To a solution of 1-butenylmagnesium bromide (0.5 M in THF, 9 mL, 4.5 mmol) at 0° C. was added a solution of 5-fluoro-2-methoxyphenylacetaldehyde (635 mg, 3.8 mmol) in THF (10 mL) dropwise for 15 min. Then the reaction mixture was poured in to a solution of saturated ammonium chloride (40 mL) in a separatory funnel. The organics were extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo and crude product thus obtained was purified by flash column chromatography (12.5% EtOAc in hexane, Rf=0.18) to give the product as an oil (642 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.Cl.[CH3:18][N:19]([CH3:30])[CH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[CH:20]([N:19]([CH3:30])[CH3:18])[CH2:21][CH2:22]2
Reactant: CN(C)C1CCc2cc(N)ccc21
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Yield: 5.5 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (256 mg, 0.90 mmol) was reacted with N1,N1-dimethyl-2,3-dihydro-1H-indene-1,5-diamine dihydrochloride (0.814 mmol) to afford the desired product (19 mg, 5.5%) as a yellow-brown solid. ESI MS m/z 424 [C22H22BrN3O+H]+