Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[CH3:32][N:33]([CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:32])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][N:41]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([S:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)(=[O:8])=[O:9])=[CH:15][CH:14]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:29])[CH2:42][CH2:43]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)C4CCOCC4)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(S(=O)(=O)C5CCOCC5)cc4)n3)cc2)CC1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
4-{4-[4-(Tetrahydropyran-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}benzoic acid 4 (0.26 g, 0.6 mmol) was dissolved in THF (5 mL). To this solution was added 1-(N,N-dimethylaminopropyl)piperazine (0.130 g), EDCI (0.136 g), and HOBt (0.096 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparative HPLC (20-70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(3-dimethylamino-propyl)piperazin-1-yl]-(4-{4-[4-(tetrahydropyran-4-sulfonyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone 5 (0.079 g, 22%): HPLC Retention Time; 7.93 min. (Method B) M+1=593.3
Reaction SMILES: C(O)C.C(O[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8])C.CC[O-].[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[OH:28][CH2:29][CH2:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8]
Reactant: OCCNC1CCCCC1
Reactant: CCOC(=O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1

Procedure:
Into 100 ml of ethanol were added 2.7 g of 6-(3-ethoxycarbonylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-(2-hydroxyethyl)cyclohexylamine and reacted in an autoclave under a pressure of 110 atomospher at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and was concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and washed with 1% K2CO3 aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. Then the solvent was removed by distillation and the residue thus obtained was purified by a silica-gel column chromatography [the silica-gel used as Wako C-200, and the solvent used was a mixture of chloroform:methanol=20:1 (V/V)]. The crude crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.9 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril as in the form colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C

Procedure:
The title compound was prepared from 3-methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-butyric acid ethyl ester (which was obtained in Example 163) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=6.8 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 1.17 (t, J=7.1 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.75–1.95 (m, 2 H), 2.05–2.20 (m, 1 H), 2.55–2.90 (m, 5 H), 2.90 (s, 3 H), 3.70–3.85 (m, 2 H), 4.00–4.20 (m, 2 H), 4.22 (t, J=7.7 Hz, 1 H), 4.48 (dd, J=8.0, 4.4 Hz, 1 H), 6.80 (d, J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 6.98 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.76 (d, J=8.9 Hz, 2 H), 8.17 (d, J=7.9 Hz, 1 H); MS (ES) m/z: 577.2 (MH+); HRMS Calcd. for C29H43N4O7S (MH+): 577.2690. Found: 577.2682.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].Cl.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1>C(OCC)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=3)=[O:4])[CH2:26][CH2:27]2)=[CH:28][CH:29]=1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-nitro-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 120-123° C. (diethylether)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>C(O)C>[CH:7]1[CH:6]=[N:5][CH:4]=[C:3]([C:1]([NH2:2])=[O:9])[CH:8]=1
Reactant: O
Reactant: N#Cc1cccnc1
Solvent: CCO
Product: NC(=O)c1cccnc1
Temperature: 87.5 °C
Yield: 95.7 %

Procedure:
In a four neck round bottom flask fitted with thermowell, agitator and reflux condenser, 3-cyanopyridine (500 g), de-mineralized water (560 g; pH 7.5), ethyl alcohol (56 g) and 40 g of fresh catalyst prepared in Example 1 were charged. The mixture was heated up to 85-90° C. for 4-6 hrs. The completion of reaction was monitored by HPLC. After the completion of reaction the crude product was cooled to 50-60° C. and filtered to separate niacinamide from the catalyst bed. The catalyst bed was washed with de-mineralized water to make catalyst free from hydrolyzed mass of 3-cyanopyridine. The wet catalyst obtained was recycled back for next batch of hydrolysis. The colorless mother liquor was concentrated and dried to get 561.5 g niacinamide. Purity: 99.6% (w/w); niacin content<0.23%; Melting Point: 128-131° C. The water layer recovered containing 3-cyanopyridine and alcohol was recycled back for next hydrolysis batch.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[S:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([N:9]4[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(S)c2N)CC1
Product: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Yield: 74 %

Procedure:
This compound was synthesized from tert-butyl 4-(5-amino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 4-fluorobenzoic acid, yielding the title compound in 74% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5](=[O:18])([O:15][CH2:16][CH3:17])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14]>S(=O)(=O)(O)O>[C:5](=[O:18])([O:15][CH2:16][CH3:17])[O:6][C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[C:9]([F:13])[C:8]=1[F:14]
Reactant: CCOC(=O)Oc1cccc(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Oc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
Step M (2): A mixture of concentrated sulfuric acid and nitric acid (1:1 ratio, 60 mL total volume) was slowly and carefully added to a solution of 2,3-difluorophenyl ethyl carbonate (20 g, 98.9 mmol) in concentrated sulfuric acid (15 mL). The internal temperature was maintained at rt throughout the addition. After complete addition, the resulting mixture was stirred for 2 h. The mixture was poured onto ice and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (hexane) to afford 2,3-difluoro-5-nitrophenyl ethyl carbonate (1.5 g, 6% yield).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][C:12](=O)[CH3:13]>C(COC)OC.C(O)C>[CH3:13][C:12]1[N:1]=[C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]2[CH:11]=1
Reactant: CC(=O)CBr
Reactant: Nc1ncccc1C=O
Solvent: CCO
Solvent: COCCOC
Product: Cc1cn2cccc(C=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-aminonicotinaldehyde (92.8 g, 0.76 mol) and bromoacetone (114.5 g, 0.84 mol) in dimethoxyethane (980 ml) is stirred for 2 hours at room temperature and then heated at 65° with stirring for 14 hours.The solid which separates is isolated by filtration, dissolved in 800 ml absolute ethanol and heated under a reflux for 6 hours. The ethanol solvent is removed under reduced pressure and the residue treated with 138ml 6 N hydrochloric acid in 750 ml water for 0.5 hour. The acidic aqueous layer is washed with ether (2×300 ml) and basified with cooling (78 ml) 50% sodium hydroxide and 25 g sodium bicarbonate). The aqueous layer is extracted with dichloromethane. The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the solvent is removed under reduced pressure to afford 2-methyl-8-formyl-imidazo[1,2-a]pyridine, mp 136°-139.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)=[CH:10][N:6]2[N:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nn1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (18.4 g, 0.14 mol) and 2-bromo-1-(4-methyl-3-nitro-phenyl)ethanone (36.13 g, 0.14 mol) in acetonitrile (219 mL) is heated at reflux for 18 hr. The mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (35.65 g, 88% yield). LCMS m/z=289.4 [M+H]+, tR=2.65 min.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:20][C:21]1[C:29]2[C:28](Cl)=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:20][C:21]1[C:29]2[C:28]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[CH:17][CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:27][CH:26]=[N:25][C:24]=2[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 72 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (370 mg, 1.46 mmol) was treated with 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (793 mg, 2.19 mmol), cesium fluoride (120 mg, 0.79 mmol), N,N-diisopropylethylamine (2.3 ml, 13.20 mol) and tert-butanol (10 ml) as a solvent according to Preparation 13. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 0.61 g (72% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20]O)[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].C(SCC(OC)C[NH2:48])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20][NH2:48])[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: CCCCCCCCCCCCCCCCSCC(CO)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)Oc1ccon1

Procedure:
3-Hexadecylthio-2-(3-isoxazolyloxy)propanol Vj1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 73°-74° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CC1CCCC1)c1nc2ccccc2nc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC1CCCC1)c1nc2ccccc2nc1CBr

Procedure:
A mixture of N-(3-methylquinoxalin-2-yl)-N-(cyclopentylmethyl)ethylamine (160 mg, 0.59 mmol), N-bromosuccinimide (130 mg, 0.73 mmol), and 2,2′-azobisisobtyronitrile (10 mg) in CCl4 is stirred and refluxed for 1 hour. The reaction mixture is purified by silica gel column chromatography to give N-[3-(bromomethyl)quinoxalin-2-yl]-N-(cyclopentylmethyl)ethylamine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:29])[O:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]([NH:21][S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:6]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[N:25]1([S:22]([NH:21][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[N:10]=[C:5]([O:4][C@H:3]([CH3:29])[CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH:6]=2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28]1
Reactant: C[C@H](CN)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-[6-((2)-2-amino-1-methylethoxy)-2-[[(2,3-Difluorophenyl)methyl]thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the title product of Example 42) (0.05 g) in dichloromethane (10 mL) was added pyridine (0.02 mL), followed by acetic anhydride (0.02 mL). The mixture was stirred overnight at room temperature. Pyridine (0.02 mL) and acetic anhydride (0.02 mL) were added and the reaction mixture was stirred for a further 2 h. Pyridine (1.0 mL) and acetic anhydride (0.50 mL) were added and the reaction mixture was stirred for a further 2 h. The reaction mixture was diluted with dichloromethane, washed with aqueous citric acid, H2O, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 40% EtOAc in isohexane as eluent. The isolated product was further purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 55 mg.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH3:2][CH:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)N
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: CCC(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 30.3 %

Procedure:
By the procedure of Example 39, a stirred mixture of 20 ml acetonitrile, 3.65 g (49.8 mmol) of sec-butylamine, and 8 g (24.9 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 16 hours. The product was separated and then triturated in hexane to yield 2.70 g of an off-white solid product (m.p.=56°-57° C.) identified in Table I.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1.O>ClCCl>[CH3:15][C:16]1([CH3:17])[C:21]([CH3:13])([CH3:20])[O:12][B:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:1][C:2]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13]3)=[O:3])=[CH:9][CH:8]=2)[O:11]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C=Nc1ccc(B(O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)OB(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)OC1(C)C

Procedure:
500 mg (4-Isocyanatophenyl)boronic acid pinacolester (1.979 mmol) and 365 mg isoindoline (2.97 mmol) were dissolved in 10 ml dichloromethane and the resultant mixture was stirred over night at room temperature. After adding water, the mixture was extracted several times with dichloromethane, the combined organic phases were washed with dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. Column chromatography of the residue with dichloromethane resulted in the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: NC1CCOCC1
Product: O=C(Nc1nc2cccc(NC3CCOCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 4-aminotetrahydropyran (Apollo), 1.0 mL) as a white powder (15 mg, 14%). 1H NMR (DMSO-d6) δ 11.27 (s, 1H), 9.13 (d, J=1.9 Hz, 1H), 8.77 (d, J=4.9, 1.5 Hz, 1H), 8.33 (dd, J=8.0, 1.9 Hz, 1H), 7.58 (m, 1H), 7.51 (t, J=8.5 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 3.88 (m, 2H), 3.80 (m, 1H), 3.45 (m, 2H), 1.89 (m, 2H), 1.72 (m, 2H). HPLC, Rt: 1.51 min. (purity 99.0%). LC/MS, M+(ESI): 339.4, M−(ESI): 337.4.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([F:39])=[C:37]([OH:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:46]=[CH:45][C:44]([C:47]2[CH:48]=[N:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:52]=2)=[CH:43][N:42]=1.[F:62][C@@H:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:64]O>C1COCC1>[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:64][C@@H:63]([F:62])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH:36]=[CH:35][C:34]=1[C:41]1[N:46]=[CH:45][C:44]([C:47]2[CH:48]=[N:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:52]=2)=[CH:43][N:42]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCCCCCCC[C@H](F)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OC[C@@H](F)CCCCCCCC)c(F)c3F)nc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
3.2 mmol of diethyl azodicarboxylate are added dropwise at 0° C. to 3.2 mmol of triphenylphosphine in 20 ml of THF, and the mixture is stirred at room temperature for a further 20 minutes. 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine and 2.4 mmol of 2-(S)-fluorodecanol are then added, and the reaction mixture is allowed to stand overnight. After the solvent has been removed in vacuo, the crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.2 g (86%) of colorless crystals, X 97 SC * 150.5 SA 161.5 I.
Reaction SMILES: [CH2:1]([C@@H:5]1[NH:11][C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3].[N:29]1[C:38]2[C:33](=[CH:34][C:35]([CH2:39][C:40](O)=[O:41])=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C@@H:5]1[N:11]([C:40](=[O:41])[CH2:39][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:29]=[CH:30][CH:31]=[CH:32]3)[C@H:10]([CH3:12])[CH2:9][CH2:8][N:7]([C@@H:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:14]([NH2:16])=[O:15])[C:6]1=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: CC(C)C[C@@H]1N[C@H](C)CCN([C@@H](Cc2ccc3ccccc3c2)C(N)=O)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(N)=O)CC[C@@H](C)N1C(=O)Cc1ccc2ncccc2c1

Procedure:
(S)-2-[(3S,5R)-3-isobutyl-5-methyl-2-oxo-[1,4]diazepan-1-yl]-3-(naphthalen-2-yl)-propionamide (382 mg, 1 mmol) is added to a solution of 6-quinolylacetic acid (372 mg, 2 mmol), Hünig's base (170 μl, 1 mmol) and EADC (383 mg, 2 mmol) in CH2Cl2 (50 ml). After 16 hours at RT the reaction mixture is extracted with 0.1 N HCl and then with 5% NaHCO3 solution. Pure title compound is isolated after silica gel chromatography using ethyl acetate —>ethyl acetate/MeOH (9/1) as mobile phase. MH+:551.4 (ESI) αD20=−12.5° (c=0.12 95% AcOH)
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([N:18]=[CH:19][C:20]([S:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([N:33]([CH3:46])S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:28]3)=[N:21]2)=[CH:16][CH:15]=1.SCCO>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([N:18]=[CH:19][C:20]([S:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][CH3:46])[CH2:31][CH2:32]3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N(C)S(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Agent: OCCS
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (36 μL, 0.24 mmol, 1.2 eq) is added at room temperature to a stirred solution of N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-N-methyl-2-nitro-benzenesulfonamide (104 mg, 0.20 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 2-mercaptoethanol (56 μL, 0.90 mmol, 1.5 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine as a yellow oil (43 mg, 62% yield).