Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(OC(C1C=CNC=1C)=O)C.[F:37]C1C=CC=CC=1CBr>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:37])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: Fc1ccccc1CBr
Agent: CCOC(=O)c1cc[nH]c1C
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 2-fluorobenzyl bromide. The title compound, ESI MS (m/z): 471 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([O:30]C)=[O:29])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1.[OH-].[Na+].Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([OH:30])=[O:29])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Yield: 95.2 %

Procedure:
Methyl [4-(2-chlorophenyl)-2-(4-{[( 1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetate (0.145 g, 0.328 mmol) was dissolved in EtOH (2 mL). NaOH (0.65 mL, 1N, 0.65 mmol) was added and the solution heated to reflux for 5 h. HCl (0.35 mL, 2N, 0.70 mmol) was added and the solvent removed. The mixture was partitioned between EtOAc and H2O. The EtOAc layer was dried (MgSO4) and the solvent removed to yield [4-(2-chlorophenyl)-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetic acid (0.138 g) as a white solid. mp 101-103° C. 1H NMR (500 MHz, DMSO-d6) δ: 0.88 (t, 6H, J=7.3 Hz), 1.50 (m, 2H), 1.55 (m, 2H), 3.42 (s, 2H), 3.82 (m, 1H), 7.35 (m, 1H), 7.42 (m, 3H), 7.58 (m, 3H), 7.96 (d, 2H, J=8.4 Hz), 8.11 (d, 1H, J=8.7 Hz). MS (ES) m/z 442.1 ([M+H]+). MS (ES) m/z 883.1 ([2M+H]+). Anal. Calcd for C24H24ClNO3S: C, 65.22; H, 5.47; N, 3.17. Found: C, 62.33; H, 5.54; N, 3.01.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][N:23]=[C:22]2[N:26]=[CH:27][CH:28]=[C:29]([CH:30]=O)[C:21]=12>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:29]4[C:21]5[C:22](=[N:23][CH:24]=[CH:25][N:20]=5)[N:26]=[CH:27][CH:28]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccnc2nccnc12
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5nccnc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and pyrido[2,3-b]pyrazine-8-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.00 (brs, 1H), 9.16-9.10 (m, 3H), 8.00 (s, 1H), 7.78 (m, 1H), 5.00-4.97 (m, 1H), 4.63-4.58 (m, 1H), 4.34-4.18 (m, 1H), 3.30 (m, 1H), 3.27 (m, 1H), 2.92-2.77 (m, 2H), 2.49-2.38 (m, 1H), 2.09-1.97 (m, 1H), 1.48 (dd, J=10.8, 6.6 Hz, 6H), 1.20 (d, J=6.6 Hz, 3H). MS: (M+H m/z 405.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[N:45][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[N:9]2[C:23]2[CH:28]=[CH:27][C:26]([C:41]3[CH:42]=[CH:43][C:44]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[N:45][CH:46]=3)=[CH:25][CH:24]=2)=[CH:4][C:3]=1[N+:30]([O-:32])=[O:31]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(I)cc2)ccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.9 %

Procedure:
(2R,5R)-2,5-Bis(4-chloro-3-nitrophenyl)-1-(4-iodophenyl)pyrrolidine (1.869 g, 3.2 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol) and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.028 g, 0.096 mmol) were combined in THF (18 mL)/water (6 mL). The mixture was purged with nitrogen for 15 minutes and stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (20% to 40%) to give the title compound (1.01 g, 51%) as a solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].[CH2:8](O)[CH:9](O)[CH3:10].S(=O)(=O)(O)O>>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]1[O:5][CH2:10][CH2:9][CH2:8][O:4]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CC(O)CO
Agent: O=S(=O)(O)O
Product: ClC(Cl)(Cl)C1OCCCO1

Procedure:
21.6 g of chloral hydrate are admixed with 9.6 g of propylene-glycol, then 16.8 ml of concentrated sulphuric acid are added. It is heated at 60°-70° C. for two hours and after dilution with 60 ml of water it is extracted two times with 60 ml of chloroform. The chloroformic phase is washed with water and sodium hydrogen carbonate, dried on magnesium sulfate, then the product is vacuum distilled after distilling off the chloroform.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].[BH4-].[Na+]>CO>[C:8]12([NH:7][C:5](=[O:6])[C:4]([CH2:3][OH:2])([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a well-stirred solution of N-adamantan-1-yl-2,2-bis-pyridin4-ylmethyl-malonamic acid methyl ester (14.92 g, 34 mmol) in methanol (175 ml), sodium borohydride (6.50 g, 172 mmol) was added portionwise over 1 hour (ambient temperature). After stirring at ambient temperature for 18 hours, the solvent was removed in vacuo, and the residue was extracted with aqueous sodium bicarbonate/chloroform (300 ml of each). The aqueous layer was then extracted three times with equal volumes of chloroform. The combined organic extracts were concentrated in vacuo to an oil (13.55 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/chloroform=4:96 in volume) afforded the (free base) title compound as an oil (7.9 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([CH3:10])=[O:9])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[C:8]([C:7]([CH3:11])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:6]([O:5][CH2:3][CH3:4])=[O:12])(=[O:9])[CH3:10]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC(=O)OCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(CCCCCOC(C)=O)C(C)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
In a 1 L three necked flask equipped with a mechanical stirrer and reflux condenser was placed dry toluene (300 ml). The system was flushed with argon and sodium hydride (Aldrich, 60% dispersion in mineral oil) (7.2 g, 1.2 eq.) was added. Ethyl-α-methylacetoacetate (Aldrich, 21 g, 0.15 mole) was added with stirring over a 30 minutes. The resulting solution was heated under reflux for 2 hours and cooled slightly. (Note: Reaction mixture becomes a thick paste and a mechanical stirrer is essential). 5-Bromopentylacetate (Aldrich, 31.5 g, 15 mol) was added (all at once) and the suspension was heated under reflux for 12 hr, cooled, filtered and the solvent evaporated under reduced pressure. The residue was distilled under vacuum to yield 20 g (45%) of colorless liquid, b.p 90-92 (0.5 mm). 1H NMR in CDCl3 δ, 4.1-4.2 (m, 2H, O—CH2CH3): 3.5 (t, J=7 Hz, 2H, CH2OCO—); 2.2 (s, 3H, CH3CO); 2.1 (s, 3H, —COCH3); 1.5-2.0 (m, 10H, 4-(CH2)2, C—CH3, OCH2CH3).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:1]([O:5][CH2:17][C:18]1[N:19]=[C:20]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CO
Reactant: CC(=O)N1CCC(c2nc(CCl)c(-c3ccccc3)o2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nc(COCC(C)C)c(-c3ccccc3)o2)CC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of isobutyl alcohol (0.54 mL, 5.8 mmol) in THF (5 mL) is cooled to 0° C. and treated with sodium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) and stirred for 1 h. A solution of 1-[4-(4-chloromethyl-5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone (1.69 g, 5.3 mmol), prepared as in Part B, in THF (30 mL) is added dropwise, and the mixture is allowed to warm to 23° C., and stirred for 18 h. The reaction mixture is partitioned between EtOAc (150 mL) and H2O (75 mL), and the organic layer is washed with brine (1×100 mL), dried (MgSO4), and concentrated. The residue is purified by chromatography on silica using EtOAc as eluent to afford the title compound as a yellow oil.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[CH:4]=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]3[C:3](=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH:4]=[N:5]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(F)c(C=NNc2ccc(F)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Yield: 36.1 %

Procedure:
1-(2-fluoro-5-methoxybenzylidene)-2-(4-fluorophenyl)hydrazine (10 g, 38 mmol) and potassium tert. butoxide (5 g, 46 mmol) was stirred under argon atmosphere in NMP (50 mL) at 150° C. for 45 min. The reaction mixture was then cooled and poured with stirring into ice-water and extracted trice with ethyl acetate. The combined organic phases were washed with water and brine, and were then evaporated. The residue crystallized slowly from methanol-water to afford 1-(4-fluorophenyl)-5-methoxy-1H-indazole as beige crystals (3.32 g, 36%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(N1CCN([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)CC1)C>>[CH2:2]1[C:43]2[C:42](=[CH:48][CH:47]=[C:45]([NH:46][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(4-ethyl-1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, 3H, J=7.1 Hz), 2.40 (q, 2H, J=7.1 Hz), 2.53-2.57 (m, 4H overlapping with d6-DMSO), 3.08-3.11 (m, 4H), 6.52 (d, 1H, J=5.2 Hz), 6.86 (d, 2H, J=9.0 Hz), 7.15 (t, 1H, J=5.7 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.46-7.54 (m, 4H), 7.62 (quintet, 1H, J=8.4 Hz), 7.85 (d, 1H, J=8.7 Hz), 8.04 (s, 1H), 8.25 (d, 1H, J=5.4 Hz), 8.47 (bd, 1H, J=8.9 Hz), 8.87 (d, 1H, J=6.9 Hz), 9.30 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=631.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(C)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 98.2 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.14 g of 4-methylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.28 g of 4-(4-methylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (28)).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][N:10]([CH:8]([C:5]2[CH:4]=[C:3]([B:28]([OH:33])[OH:29])[C:2]([F:1])=[N:7][CH:6]=2)[CH3:9])[CH2:15][CH2:14]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (8.41 g, 27.2 mmol) in tetrahydrofuran (100 mL) was chilled to −78° C. in a dry ice/acetone bath. Then n-butyllithium (1.6 M in hexanes; Aldrich; 18.69 mL, 29.9 mmol) was added via cannula into the mixture. The deep red solution was stirred at the same temperature for 1 h, then triisopropyl borate (7.50 mL, 32.6 mmol) was added into the mixture. The resulting mixture was stirred at the same temperature (−78° C.) for 30 min, then the ice bath was removed. After the reaction mixture warmed up to room temperature, the tan mixture was quenched with 1 N NaOH(aq) (50 mL) and stirred 10 min. The separated aqueous layer was collected and the round-bottomed flask was rinsed with 1 N NaOH(aq) (2×10 mL). The aqueous layer was carefully acidified with 10% HCl until acidic (about pH 5 to 6) and the resulting cloudy mixture was extracted with 3:1 dichloromethane/methanol (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. This gave 5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (5.507 g, 15.59 mmol, 57.4% yield) as tan solid. 1H NMR (400 MHz, d6-DMSO) δ 7.79-8.70 (m, 2H) 3.66 (t, J=6.36 Hz, 1H) 3.34 (s, 4H) 2.56 (s, 3H) 2.39 (s, 4H) 1.26-1.51 (m, 12H). m/z (ESI, +ve ion) 354.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH:60][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 67 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in tetrahydrofuran. Yield: 67%; Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1); C23H25ClN4O2 (424.93); mass spectrum: (M+H)+=425/427 (chlorine isotope).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[OH:21])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:29]([CH3:31])[CH3:30]>C(C(C)=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH:29]([CH3:31])[CH3:30])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)(C)c1cc(C(=O)OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)Oc1ccc(C(=O)OCc2ccccc2)cc1C(C)(C)C

Procedure:
5.7 g (0.02 mol) of benzyl 3-tert-butyl -4-hydroxybenzoate, 7 g (0.05 mol) of finely ground potassium carbonate, 4 ml (0.04 mol) of 2-iodopropane and 100 ml of methyl ethyl ketone are introduced under nitrogen into a three-necked flask. The mixture is heated to reflux for 24 h, the inorganic matter is filtered off and the filtrate is evaporated. The residue is taken up with ethyl ether and water and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[NH:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(I)cc1C)C(=O)OC(C)(C)C
Reactant: O=C1CCCN1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(N2CCCC2=O)cc1C)C(=O)OC(C)(C)C
Yield: 89.3 %

Procedure:
The compound (650 mg, 1.00 mmol) of Example 293, step A, 2-pyrrolidone (128 mg, 1.50 mmol), copper iodide(I) (19 mg, 0.10 mmol), N,N′-dimethylethylenediamine (0.022 ml, 0.20 mmol) and potassium phosphate (425 mg, 2.00 mmol) were dissolved in toluene (4.0 ml), and the mixture was heated under reflux for 7 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (542 mg, yield 89%) as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+]=[N-])#[N:2].C(N(CC)CC)C.C(S)CCS>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[NH2:15])#[N:2]
Reactant: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Yield: 95.9 %

Procedure:
A solution of trans-5-cyano-1,1-dimethyl-3-azido-indan-2-ol (0.93 g), triethylamine (1.2 ml) and 1,3-propanedithiol (0.9 ml) in dry methanol (20 ml) was stirred at room temperature for 48 h. After filtration, the solution was evaporated in vacuo to give the title compound (0.79 g) as a gum.
Reaction SMILES: [CH2:1]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CCCC)=[O:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>CO>[CH2:1]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN1CCN(c2ccc(CCC(=O)OCCCC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCN1CCN(c2ccc(CCC(=O)O)cc2)CC1

Procedure:
A mixture of 16.0 g. (30 mmole) n-butyl 3-[4-(1-n-hexadecylpiperazin-4-yl)-phenyl]-propionate, 125 ml. 1N aqueous sodium hydroxide solution and 125 ml. methanol is stirred for 6 hours at 60° C. and the methanol subsequently distilled off. Crystals precipitate out from the cold aqueous phase, which are filtered off with suction and washed with water. They are dissolved in hot water and the hydrochloride is precipitated with 2N hydrochloric acid. After suction filtration, washing with water and drying, the yield is 13.0 g. (85% of theory); m.p. 218°-220° C. When recrystallised from methanol, with the addition of a little water, the hydrochloride melts at 219°-221° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:20]>>[OH2:20].[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(SCc3ccccc3N)nc12
Solvent: O
Product: Cc1cccc2[nH]c(S(=O)Cc3ccccc3N)nc12

Procedure:
The title compound (740 mg) was prepared by the method of Example 3 using 900 mg of the title product of Example 7 instead of the title product of Example 2. Anal. Calc'd. for C15H15N3S*1/2 H2O: C, 61.20; H,5.48; N, 14.27; S, 10.89. Found: C, 61.21; H, 5.05; N, 13.88; S, 11.12.