Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[O:21][N:20]=1>>[F:30][C:28]1[CH:29]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:5]3[C:6]4[C:11](=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:23]=2)[CH:25]=[C:26]([F:31])[CH:27]=1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.75-7.62 (m, 4H), 5.94 (s, 2H), 3.06 (t, 2H), 1.77-1.65 (m, 2H), 0.95 (t, J=7.3 Hz, 3H): MS (ES) m/z 404 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([O:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])[CH2:17][CH2:16]2)=[CH:21][CH:22]=1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@@H](O)CC2)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture 3.5 g (13.8 mmol) of cis-(4-Isopropyl-piperazin-1-yl)-(4-hydroxycyclohexyl)-methanone, 2.35 g (15.4 mmol) of methyl 4-hydroxybenzoate, 4.47 g (17.0 mmol) of triphenylphosphine in 12 ml of THF, a mixture of 3.88 g (16.9 mmol) of di-tert-butyl azodicarboxylate in 13 ml of THF was added dropwise at 0° C., and stirred for 24 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and methanol=from 98:2 to 9:1. After evaporation of the combined products, the residue was purified by column chromatography on silica gel eluting with CH2Cl2 and MeOH=from 100:0 to 19:1. The combined product fractions were evaporated to dryness to yield 1.34 g (25%) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester. A mixture of 0.6 g (1.5 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid methyl ester, 42 mg (1.8 mmol) of lithium hydroxide, 6 ml of THF, 3 ml of water, and 1 ml of methanol was stirred at 80° C. for 16 h. After evaporation, the residue was acidified with 2N hydrochloric acid solution and evaporated. The precipitate was washed with water and dried to yield 0.56 g (97%) of the titled compound. MS (m/e): 375 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH:21][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(5-Amino-1-benzenesulfonyl 1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.12 mmol), isobutyryl chloride (225 mg, 2.12 mmol) and triethylamine (590 μL, 4.24 mmol) in DCM (15 mL) were stirred at ambient temperature for 2 hours. The mixture was diluted with DCM, washed with a saturated sodium hydrogen carbonate solution, water and brine, dried through a phase separator and concentrated under vacuum affording 4-(1-benzenesulfonyl-5-isobutyrylamino-1H-pyrrolo[2,3-b]pyridine-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a brown residue which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.77 min, m+H=542.36.
Reaction SMILES: [Li][CH2:2]CCC.Br[C:7]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([F:17])[C:8]=1[C:9]([OH:11])=[O:10].C=O>CCOC(C)=O>[Br:16][C:14]1[CH:13]=[C:12]([F:17])[C:8]2[C:9](=[O:10])[O:11][CH2:2][C:7]=2[CH:15]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1Br
Reactant: [Li]CCCC
Agent: C=O
Solvent: CCOC(C)=O
Product: O=C1OCc2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of n-BuLi (36.7 mL, 91.6 mmol) was added dropwise to a solution of 2,4-dibromo-6-fluorobenzoic acid (13.0 g, 43.6 mmol, in 200 mL of THF) at −70° C. The resulting solution was stirred for 15 minutes before CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture at −70° C. The suspension was stirred for 1 hour then warmed to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a clear solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=5:1) to give 5-bromo-7-fluoro-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])=O>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:3]=1[CH2:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([C:31]([OH:33])=[O:32])[C:26]=1[CH3:34])(=[O:6])=[O:7]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cc(Cl)ccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O

Procedure:
5-[(2,5-Dichlorobenzyl)sulfonyl]-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid to give the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:16][C@@H:15]([C:17]([OH:19])=O)[C@H:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:13]1)(=[O:11])=[O:10].[NH2:29][CH2:30][C:31]#[N:32]>>[C:30]([CH2:31][NH:32][C:17]([C@@H:15]1[CH2:16][CH:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:19])#[N:29]
Reactant: N#CCN
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1
Product: N#CCNC(=O)[C@@H]1CC(S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 11 using (1R,2R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture, example 143 and 144 step 6) and aminoacetonitrile. Light yellow foam gum (44%). MS (EI): 469.3 (M+H)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2([CH2:63][CH2:64][CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]4OCC[O:74]4)[CH:68]=3)[C:28]3[CH:27]=[C:26]([N:29]([C:36]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][C:19]([N:46]([C:53]2[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=1.Cl>CC(C)=O>[C:36]1([N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([N:46]([C:53]5[C:62]6[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=6)[CH:56]=[CH:55][CH:54]=5)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[CH:20][CH:21]=4)[C:16]([CH2:63][CH2:64][CH2:65][CH2:66][C:67]4[CH:68]=[C:69]([CH:70]=[CH:71][CH:72]=4)[CH:73]=[O:74])([CH2:15][CH2:14][CH2:13][CH2:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[CH:2]=[O:1])[C:28]=3[CH:27]=2)[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc(N(c2ccc3c(c2)C(CCCCc2cccc(C4OCCO4)c2)(CCCCc2cccc(C4OCCO4)c2)c2cc(N(c4ccccc4)c4cccc5ccccc45)ccc2-3)c2cccc3ccccc23)cc1
Agent: Cl
Solvent: CC(C)=O
Product: O=Cc1cccc(CCCCC2(CCCCc3cccc(C=O)c3)c3cc(N(c4ccccc4)c4cccc5ccccc45)ccc3-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc32)c1
Reaction time: 0.5 h

Procedure:
To 1-liter three-neck round bottom flask equipped with a magnetic stir bar and an addition funnel was transferred a solution of 9,9-bis(4-(3-(1,3-dioxolan-2-yl)phenyl)butyl)-N2,N7-di(naphthalen-1-yl)-N2,N7-diphenyl-9H-fluorene-2,7-diamine (12.3 g) in acetone (500 mL). Hydrochloric acid solution (61.0 mL, 2.0M) was transferred to the addition funnel atop the reaction flask by syringe. The acid solution was added to the reaction dropwise with vigorous stirring. The reaction was allowed to stir for an additional 30 minutes following the addition of acid. Reaction completion was confirmed by thin-layer chromatography and solvent was removed by rotary evaporation. Ethyl acetate (750 mL) was added to the resulting mixture and this solution was washed with DI water (5×200 mL). The organic fraction was collected and dried over anhydrous magnesium sulfate. Solids were removed by gravity filtration. Silica gel was added to the solution and solvent was removed by rotary evaporation leaving the crude material adsorbed to silica. Crude product was initially purified by flash column chromatography using ethyl acetate/hexane as an eluent. The resulting material was dissolved in a minimum amount of acetone and precipitated into cold methanol (3×750 mL). The solids collected by vacuum filtration were dried and determined to be pure product by NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([S:32][C:30](=[O:33])[CH3:31])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)Sc1ccc(C2CN(CCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a degassed solution of 3-[2-(4-trifluoromethanesulfonyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (2.55 g; 5.80 mmol) in toluene (50 mL) was added Pd2dba3 (0.27 g; 0.29 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]-ethyl]-2-(dicyclohexylphosphino)ferrocene (0.32 g; 0.58 mmol), followed, after 5 min. by, potassium thioacetate (1.33 g; 11.6 mmol). The resulting mixture was heated under reflux overnight. After cooling to RT the mixture was diluted with CH2Cl2, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/acetone 95:5) to afford 3-[2-(4-Acetylsulfanyl-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (1.70 g)
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21](F)[C:22]=3[Cl:24])[C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15]2)[N:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:21]2[C:22]([Cl:24])=[C:23]3[C:18]([C:17](=[O:27])[C:16]([C:28]([OH:30])=[O:29])=[CH:15][N:14]3[C:9]3[N:8]=[C:7]([NH2:6])[C:12]([F:13])=[CH:11][N:10]=3)=[CH:19][C:20]=2[F:26])[CH2:35]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ncc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ncc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To 100 mg of N,N-dimethylformamide were added 25 mg of 1-(4-amino-5-fluoropyrimidine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride, and 50 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 10 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([CH:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH2:8][S:7]1)[CH3:5].S(Cl)(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH3:5]
Reactant: CC(C)CC(C)C1SCC=C1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)CC(C)c1sccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
After dissolving 2.8 g of 2-(4-methylpentan-2-yl)-3-nitro-2,5-dihydrothiophene in 40 ml of dichloromethane, a solution prepared by dissolving 2.6 g of sulfuryl chloride in 5 ml of dichloromethane was added thereto, and the solution was stirred at room temperature for 1.5 hours. After adding an aqueous solution of saturated sodium bicarbonate, the solution was extracted with dichloromethane. The organic layer was washed with saturated saline, dried with magnesium sulfate and concentrated, and then purified by NH-silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 2.0 g of 2-(4-methylpentan-2-yl)-3-nitrothiophene (yield: 70.1%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C[O:17][C:18]([C:20]#[C:21][C:22]([O:24]C)=[O:23])=[O:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15]/[C:20](=[CH:21]\[C:22]([OH:24])=[O:23])/[C:18]([OH:19])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(O/C(=C\C(=O)O)C(=O)O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 2060 parts of 2,4-di-t-butylphenol, 1040 parts by volume of acetylene dicarboxylic acid dimethyl ester and 10 parts of benzyltrimethylammonium hydroxide was heated on a steam bath until a rapid exothermic reaction had occurred. The mixture was cooled to room temperature and ether was added. The ether extract was washed with N sodium hydroxide solution, sodium chloride solution and water, then the ether was removed by evaporation. The residue obtained was refluxed for three hours with 5000 parts of 5N sodium hydroxide solution. After cooling the mixture to room temperature, the solid which precipitated was removed by filtration.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8](O)=[N:7][C:6]=2[NH:5][N:4]=1)[CH3:2].P(Br)(Br)([Br:20])=O>C(#N)C>[Br:20][C:8]1[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:11]2[C:3]([CH2:1][CH3:2])=[N:4][NH:5][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(CC)c12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(CC)c12
Yield: 68.3 %

Procedure:
Ethyl 3-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.52 g, 2.21 mmol) was suspended in acetonitrile (6 mL) and POBr3 (1.27 g, 4.42 mmol) was added to it. The reaction mixture was refluxed for 6 h. On completion of reaction, acetonitrile was removed under reduced pressure and residue neutralized with saturated NaHCO3. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired intermediate (0.45 g, 68.5%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]([CH2:14][C:15](O)=[O:16])[C:11]([OH:13])=[O:12]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:15](=[O:16])[CH2:14][CH:10]([C:11]([OH:13])=[O:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Temperature: 170 °C
Reaction time: 0.25 h

Procedure:
A 250 mL round-bottomed flask was charged with 4-fluoroaniline 50 (12.8 g, 115 mmol) and 2-methylenesuccinic acid 49 (15.0 g, 115 mmol). The flask was fitted with a reflux condenser then heated at 170° C. Once at that temperature, heating was continued for 15 min. After that time, the molten mass was cooled to room temperature and water was added. The resulting precipitate was filtered then dissolved in 2 N NaOH. The solution was filtered again and the filtrate was acidified using concentrated HCl. The resulting precipitate was collected by filtration and dried at 70° C. under vacuum to give 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid 51.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:8])[CH2:5][CH2:6][CH3:7].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: CCCC(O)CCC
Product: CCCC(CCC)Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from heptan-4-ol and 2-amino-6-fluorobenzonitrile as a white solid (24%). 1H NMR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 6H), 1.55-1.31 (m, 8H), 3.88 (s, br, 1H), 4.33-4.27 (m, 1H), 6.26 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[C:14]=S>>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]2[CH2:3][CH2:4][O:5][C:14]([NH:13][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[N:26]=[CH:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=5)[N:23]=4)=[CH:20][CH:21]=3)=[N:1]2)=[CH:11][CH:10]=1
Reactant: NC(CCO)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccc(Cl)cc5)CCO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 3-amino-3-(4-chlorophenyl)propan-1-ol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.150 g, 64%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].ClC1C=CC=C(C(OO)=[O:17])C=1.C(OCC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][O:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: BrCCCCCC1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
7-Bromo-1-heptene (5.10 g) was dissolved in chloroform (29 ml), the solution was added with m-chloroperbenzoic acid (6.21 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with diethyl ether and saturated aqueous sodium thiosulfate, the layers were separated, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under ordinary pressure to obtain the title compound (5.27 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[C:24](Cl)(=[O:26])[CH3:25]>[N+](C)([O-])=O>[C:24]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:14][C:6]([NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:5])[CH2:7]2)(=[O:26])[CH3:25]
Reactant: CC1(NC(=O)c2ccccc2)Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
Aluminium chloride (3.7 g) is dissolved in nitromethane (12 ml) under nitrogen followed by N-(2-methyl-indan-2-yl)-benzamide (3.0 g) at 0° C. Acetyl chloride (0.85 ml) is added dropwise over 30 minutes. After 4 hours at room temperature the mixture is quenched with ice and concentrated HCl, extracted with DCM. The organic layers are washed with dilute HCl and brine. Evaporation of the solvent yielded the desired product. ES+ MS m/e 294 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(#N)C>[O:28]([CH2:27][CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCOc1ccccc1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nccc2cc(OC3CCCN(CCOc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of 6-(piperidin-3-yloxy)isoquinolin-1-ylamine (30 mg, 123 μmol) in DMF (1 ml) was added potassium carbonate (18 mg, 129 μmol) followed by a solution of (2-bromoethoxy)benzene (26 mg, 129 μmol) in acetonitrile (0.5 ml). The mixture was stirred for 16 h at ambient temperature, then the solvent removed in vacuo and aqueous sodium hydrogen carbonate added. The mixture was extracted with chloroform/iso-propanol (3:1), dried (magnesium sulphate) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-[1-(2-phenoxyethyl)piperidin-3-yloxy]-isoquinolin-1-ylamine (12.5 mg) El-MS: m/z=364.8 [M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C1COCC1>[N:35]1([C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(N3CCCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Example 20) (30 mg, 0.06 mmol) was reacted with excess piperidine (0.5 mL) in THF in a sealed tube at 60° C. overnight by general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=546 (M++1); Rt=5.36 min. 1H-NMR 400 MHz (CDCl3); δ 0.85-0.95 (m, 2H), 1.71-1.59 (m, 2H), 1.60-1.69 (m, 2H), 3.55-3.65 (s, 4H), 6.89-6.94 (m, 1H), 7.08-7.21 (m, 8H), 7.35 (d, J=2 Hz, 1H).