Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH2:16])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].C(#N)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(N(CC)CC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2]
Reactant: C=CCC(CCCC#N)CCC(=O)OCC
Reactant: Brc1cccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N

Procedure:
A mixture of 1300 g of ethyl 4-(3-cyanopropyl)-6-heptenoate, 6397 ml of acetonitrile, 3190 mL of triethylamine and 920.9 g of 3-bromopyridine is degassed and then heated to reflux. Palladium II acetate catalyst (13 g) and 36.42 g of tri-o-tolylphosphine are added and the mixture is heated under reflux overnight. Additional catalyst (13 g) is added and the mixture is again heated under reflux for 7 hours. Further catalyst (6.5 g) is again added and the reaction is again heated under reflux overnight. The reaction mixture is cooled, diluted with 6 L of methylene chloride, and evaporated to dryness. The residue is partitioned between ether and water. The ether layer is separated and the aqueous layer is extracted two more times with ether. The combined ether extracts are extracted with 2×8 L of 1 N hydrochloric acid. The acid extract is cooled and made basic with 1200 ml of conc. ammonium hydroxide to pH 10, and extracted with ether (3×8 L). The ether extract is dried over sodium sulfate and evaporated to dryness to yield ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH2:11])[CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[C:14]=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(N=C=O)c1

Procedure:
In analogy to the procedure described in example 9.1, 3-amino-4-methyl-benzoic acid methyl ester ([18595-18-1]) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 16 h to give the title compound as brown solid which was used in the next step without further purification. MS: m/e=191 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:37][CH:36]=3)=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carboxylic acid in 10 ml of DMF was added 900 mg of 4-chlorobenzoic acid hydrazide, 1.1 g of EDCI and 700 mg of HOBT. The reaction was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture was diluted with water and the resulting precipitates were collected by filtration and purified by column chromatography (DCM:MeOH=20:1) to give the title compound. LCMS ret T=1.19 min, m/z=504.1, Method 10.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:11]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)[CH:34]=[CH:33][C:32]=1O>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:10]3[CH:11]=[C:7]([CH2:6][O:5][C:32]4[CH:33]=[CH:34][C:35]([N:37]5[CH:41]=[N:40][N:39]=[N:38]5)=[CH:36][C:31]=4[F:30])[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9]3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1
Reactant: Oc1ccc(-n2cnnn2)cc1F
Product: CCc1cnc(N2CCC(n3cc(COc4ccc(-n5cnnn5)cc4F)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl methanesulfonate and 2-fluoro-4-(1H-tetrazol-1-yl)phenol in a manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.99 (1H, s), 8.15 (2H, s), 7.64 (1H, s), 7.50 (1H, m), 7.41 (1H, m), 7.17 (1H, m), 5.13 (2H, s), 4.86 (2H, m), 4.42 (1H, m), 2.99 (2H, m), 2.44 (2H, q), 2.20 (2H, m), 1.93 (2H, m), 1.16 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C@@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:53][C@@H:54]2[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]2[OH:60])=[O:15])=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
5-(4-Chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (21.5 g, 0.071 mol) was dissolved in DMF (655 mL). To the solution was added TBTU (25 g, 0.078 mol), N,N-diisopropylethyl amine (60.5 mL, 0.35 mol) and (1R,2R)-2-amino-cyclohexanol (11.8 g, 0.078 mol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 21.7 g of the title compound as a white solid, MS (ISP) 401.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:17])=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 73 %

Procedure:
A mixture solution of 2.2 g of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid, 1.67 ml of 1-benzyl-4-aminopiperidine, 10.47 g of 25% propane-phosphonic acid anhydride and 4.76 ml of triethylamine in 40 ml of methylene chloride was stirred over night at room temperature. Then, 20 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 2.48 g (73%) of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]-N-(1-benzyl-4-piperidinyl)acetamide. Then, a mixture of 438 mg of the compound obtained and 40 mg of 20%-palladium hydroxide on carbon in 4 ml of methanol was stirred for 6 hours under 5 atm of hydrogen. Then, the catalyst was filtered off a Celite (trade name) pud and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=10:1) to give 293 mg (81%) of the above-mentioned compound (21).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:13]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Cc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C
Yield: 3.9 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-toluidine (1.25 g, 11.7 mmol) in 10 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol and recrystallized from acetonitrile-DMF to yield 0.11 g of the title compound, mp 224°-225° C (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of ethyl 3-(2-fluorophenyl)-3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(2-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (25.7 g, 73%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13]Br>O1CCOCC1.N#N.ClC(Cl)C>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:5]=1
Reactant: Cn1ccnc1N1CCOCC1
Reactant: BrBr
Agent: N#N
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1c(Br)cnc1N1CCOCC1
Temperature: 60 °C
Yield: 31 %

Procedure:
4-(1-Methyl-1H-imidazol-2-yl)-morpholine (Nagarajan, K. et al. Indian J. Chem. Sect. B, 21, 10, 1982, 949–952) (1.02 g, 6.08 mmol) was dissolved in 35 mL of 1,4-dioxane under and N2 atmosphere. The mixture was heated to 60° C. and a solution of 0.34 mL (6.4 mmol) of Br2 in 10 mL of dichloroethane was added slowly. The mixture was heated for 1 h, then cooled. The mixture was concentrated and the residue was partitioned between 6.5 mL of 1 N NaOH and 25 mL of EtOAc. The NaOH solution was extracted twice more with EtOAc, and the extracts were washed with NaHCO3 and brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–4% MeOH (0.5% NH4OH) in CH2Cl2) to provide 464 mg of 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-leucine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-leucine, ethyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:17][C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1OC1CCCCC1
Yield: 47 %

Procedure:
Following the procedure for Example 230 reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and cyclohexanol gave 5-(cyclohexyloxy)-1-methyl-4-nitro-1H-pyrazole as off-white solid (132 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 4.76-4.67 (m, 1H), 3.70 (s, 3H), 2.10-2.02 (m, 2H), 1.85-1.78 (m, 2H), 1.64-1.52 (m, 2H), 1.43-1.22 (m, 3H), 0.96-0.81 (m, 1H)
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[Cl:19][C:20]1[N:24]=[C:23]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:18][CH:17]=3)[CH2:16][CH2:15]2)[S:22][N:21]=1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CCN2CCN(c3nc(Cl)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-methoxyphenethyl)piperazine dihydrochloride (1.04 g, 3.55 mmol), 3,5-dichloro-1,2,4-thiadiazole (500 mg, 3.23 mmol) and DIPEA (1.33 g, 1.8 ml, 10.3 mmol) in 23 mL EtOH was stirred for 1 h at RT. The reaction solution was concentrated in vacuo and the crude product was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc to yield, after evaporation of the product containing fraction, 1.06 g (97%) of the title compound as white solid. MS (m/e): 339.2 (MH+).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CCOCC>C1C=CC=CC=1>[CH2:5]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCc1ccccc1CO
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCc1ccccc1CBr
Temperature: 0 °C

Procedure:
A solution of 10 g of phosphorus tribromide in 50 ml of benzene is added dropwise over a period of 15 minutes to a stirred mixture of 6.6 g of 2-nonylbenzyl alcohol and 50 ml of benzene. The reaction mixture is heated under reflux for 30 minutes and, after cooling, ice-water and ether are added. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. Chromatographic purification of the residue on silica gel with petroleum ether yields 2-nonylbenzyl bromide in the form of a colourless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][O:35]CCO)=[CH:30][CH:29]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(NCC)C>C(Cl)Cl>[NH:13]([C:20]1[C:25]([Br:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][O:35][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:32][CH:33]=2)[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and methanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0-2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1
Reactant: OCC1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
A portion (0.7 g) of the 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 4 was dissolved in 50 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (1 g), water (3 ml) and concentrated sulfuric acid (1.4 g) was added dropwise over time, and the solution was stirred for 6 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized with acetone-water, yielding 0.4 g of 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 241.5°-243.5° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(Cl)c3)CC12
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-chlorophenylacetic acid (1.19 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (100 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-chlorophenyl)acetyl]-4-perhydroisoindolone (2.2 g) is obtained in the form of white crystals melting at 179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([O:18]C)=[O:17].C[Si](C)(C)[O-].[K+].[ClH:26]>C(OCC)C.O1CCOCC1>[ClH:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([OH:18])=[O:17]
Reactant: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCN1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl (3S,4R)-4-(2,4-difluorophenyl)-1-ethylpyrrolidine-3-carboxylate, from preparation 18 (5.9 g, 22 mmol) in diethyl ether (59 mL) at room temperature under dry nitrogen was added potassium trimethylsilanolate (2.36 g, 26 mmol) in a single portion. The resulting mixture was stirred at room temperature under N2 for 3 hours. A solution of 4M hydrogen chloride in dioxane (20 mL) was then added and the resulting mixture was stirred under dry nitrogen at room temperature for 18 hours, and then concentrated in vacuo to afford the title compound as a white solid containing potassium chloride residues (7.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(O)CCCCC.[OH-].[Na+].[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>C(OC(C)C)(=O)C>[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].[CH3:13][O:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCCNCCCl
Reactant: COc1cc(N)c2ncccc2c1
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Solvent: CC(=O)OC(C)C
Product: COc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 145 °C
Reaction time: 21 h

Procedure:
A mixture of 8-amino-6-methoxyquinoline (150.0 g, 0.862 mol) and bis(2-chloroethyl)amine (219 g, 1.23 mol,) in 6 parts (volume of hexanol vs weight of 8-amino-6-methoxyquinoline) of 1-hexanol (900 mL) was heated to 145° C. and stirred for 21 hours. Upon completion, the reaction mixture is cooled 50-60° C., and 507 g of aqueous NaOH solution was added slowly. The reaction mixture was cooled to 25-30° C. and isopropyl acetate (750 mL) was added. The mixture was clarified through a celite pad. The aqueous phase was then split off. The organic solution was treated with a slurry of adipic acid (126 g, 0.862 mol) in isopropyl acetate (250 ml). The resulting mixture was stirred for 16 hours to form 6-methoxy-8-(1-piperazinyl)quinoline adipate salt. The adipate salt was filtered and washed with isopropyl acetate (2×150 ml) and dried by nitrogen flow to give adipate of 6-Methoxy-8-piperazin-1-yl-quinoline (186 g, 55% yield) with ˜97% HPLC area, 88% strength purity in 51% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][O:18]C1N=CC(B(O)O)=CN=1>>[CH3:17][O:18][C:16]1[N:13]=[CH:12][C:11]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])=[CH:15][N:14]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: COc1ncc(-c2ccc(C)cc2C(=O)O)cn1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (2-methoxypyrimidin-5-yl)boronic acid. ESI-MS (m/z): 245 [M+1]+.