Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:40][CH2:41][OH:42]>CCO.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:40][CH2:41][OH:42])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: OCCCl
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(NC(COCC1CCN(CCO)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 31.7 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (200 mg, 0.45 mmol) in 5 mL of EtOH was added potassium carbonate (247 mg, 1.8 mmol), potassium iodide (224 mg, 1.4 mmol) and 2-chloroethanol (0.09 mL, 1.4 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 10:0.5 EtOAc:isopropylamine) provided 70 mg (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:23])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](O)=[O:21])=[N:12]3)[C:4]=2[O:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:46][NH:47][O:48][CH3:49].CCN(CC)CC>CN(C=O)C.O>[F:23][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([N:47]([O:48][CH3:49])[CH3:46])=[O:21])=[N:12]3)[C:4]=2[O:3]1
Reactant: CNOC
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a mixture of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 12 mmol), HOBt (2.7 g, 17 mmol) and WSC (3.4 g, 17 mmol) in DMF (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) and Et3N(4.9 mL, 35 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL×2). The combined organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give orange crystals. The crystals were washed with AcOEt/hexane (1/4) to give the title compound (2.7 g, 62% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.96 (3H, s), 7.12 (1H, dd, J=7.9, 1.1 Hz), 7.23 (1H, d, J=8.7 Hz), 7.57 (1H, dd, J=8.7, 1.1 Hz), 8.06 (1H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>>[C:30]([CH2:32][C:33]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)=[O:34])#[N:31]
Reactant: N#CCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)CC#N)C3)cc1

Procedure:
Compound ex was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-cyanoacetyl chloride. LC-MS: m/z=+464 (M+H)+.
Reaction SMILES: C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])(=O)C.[K+].[NH2:40][C:41]1[C:45]([C:46]([NH2:48])=[O:47])=[CH:44][NH:43][N:42]=1.Br[C:50]1[CH:61]=[CH:60][C:53]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])=[CH:52][CH:51]=1>CCOC(C)=O.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].CC(O)C>[C:46]([C:45]1[C:41]([NH:40][C:50]2[CH:61]=[CH:60][C:53]([C:54]([O:56][CH:57]([CH3:58])[CH3:59])=[O:55])=[CH:52][CH:51]=2)=[N:42][NH:43][CH:44]=1)(=[O:47])[NH2:48]
Reactant: CC(C)OC(=O)c1ccc(Br)cc1
Reactant: NC(=O)c1c[nH]nc1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1ccc(Nc2n[nH]cc2C(N)=O)cc1
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A round-bottomed flask was charged with 2-propanol (595 mL), and nitrogen was bubbled through the 2-propanol for 2 hours. Pd2(dba)3 (1.63 g, 1.78 mmol) and di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (3.43 g, 7.14 mmol) were added, and the mixture was stirred for 20 minutes. Potassium acetate (17.5 g, 178 mmol), 3-amino-1H-pyrazole-4-carboxamide (15.0 g, 119 mmol), and isopropyl 4-bromobenzoate (34.7 g, 143 mmol) were then added, and the reaction mixture was heated to 75° C. for 6.5 hours. The reaction mixture was then cooled to 23° C., diluted with EtOAc (500 mL), and filtered through celite. The filtrate was adsorbed onto silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 30-90%, EtOAc/hexanes) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@H]1CCNC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CC[C@H](O)C1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A stirred solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (102 mg, 0.194 mmol), (S)-3-pyrrolidinol (51 mg, 0.582 mmol), N,N-diisopropylethylamine (75 mg, 0.582 mmol) and tetrabutylammonium iodide (71 mg, 0.194 mmol) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. for 20 h. After cooling to room temperature, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was separated, washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (using a phenyl-hexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O). The combined fractions were washed with saturated aqueous NaHCO3 and the aqueous layer extracted with a mixture of 20% methanol in dichloromethane (2×50 mL). Concentration under reduced pressure afforded (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (16 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.59 (brs, 1H), 7.68 (brs, 1H), 7.52-7.55 (m, 2H), 7.26-7.35 (m, 4H), 6.95 (m, 1H), 6.11 (s, 1H), 4.34-4.40 (m, 3H), 4.04 (s, 3H), 3.00-3.20 (m, 2H), 2.84 (m, 1H), 2.67-2.68 (m, 2H), 2.50 (m, 1H), 2.10-2.30 (m, 3H), 1.80 (m, 1H), 1.51 (m, 1H), 1.26 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]1[N:19]([CH2:20][C:21](OCC)=[O:22])[CH:18]=[N:17][CH:16]=1)=[CH:10][CH2:9][CH2:8]2)#[N:4]>C(O)C>[OH:22][CH2:21][CH2:20][N:19]1[C:15]([C:11]2[C:12]3[CH:13]=[CH:14][C:5]([C:3]#[N:4])=[CH:6][C:7]=3[CH2:8][CH2:9][CH:10]=2)=[CH:16][N:17]=[CH:18]1
Reactant: CCOC(=O)Cn1cncc1C1=CCCc2cc(C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2c(c1)CCC=C2c1cncn1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.0 mmol of sodium borohydride are added in portions to a solution of 19.5 mmol of ethyl [5-(6-cyano-3,4-dihydronaphthalen-1-yl)imidazol-1-yl]acetate in 150 ml of ethanol at 0° C. The reaction mixture is stirred at room temperature for 2 hours and then evaporated. The residue is taken up in saturated aqueous sodium bicarbonate solution, and dichloromethane is added to the mixture. The reaction mixture is stirred at room temperature for 10 minutes and the phases are separated. The aqueous phase is back-extracted with dichloromethane, and the combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60F). Rf=0.16 (dichloromethane-methanol-25% aqueous ammonia solution 200:20:1); Rt=5.04 (gradient II).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][OH:13])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].NCC(O)CO>C1(C)C=CC=CC=1.COCCOC.O1CCCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:9][S:8][C:6]1[N:5]=[C:4]([NH:10][CH2:11][CH2:12][OH:13])[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)[N:7]=1
Reactant: CSc1nc(Cl)cc(NCCO)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NCC(O)CO
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C
Yield: 33 %

Procedure:
To a mixture of 2-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl-amino)-ethanol (404 mg), 3-(trifluoromethyl)phenyl boronic acid (384 mg) and sodium carbonate (585 mg) in toluene (12 ml) with a few drops of DME and ethanol, was added Pd(PPh3)4 (106 mg). The resulting suspension was subjected to microwave heating at 150° C. for 20 mins. Reaction mixture was filtered through a celite pad, washed with ethyl acetate and concentrated in vacuo. The residual brown gum was columned on silica gel using heptane and ethyl acetate (1:1) as eluant. Product obtained was dissolved in tetrahydrofuran and stirred with 3-amino-1,2-propanediol at room temperature for 30 mins then diluted with ethyl acetate (40 ml) and washed with 1M hydrochloric acid (2×100 ml), brine (40 ml), dried over MgSO4 and concentrated in vacuo to give 200 mg of 2-[2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl-amino]-ethanol as a brown gum. Remaining acidic aqueous layer was slowly neutralised and the resulting white precipitate was filtered and dried. This generated 2-[2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl-amino]-ethanol as a white solid (450 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])[C:5]([Cl:12])=[CH:4][N:3]=1.[N+:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:5]1[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=[N:7][C:2]([O:23][C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]=2[CH3:24])=[N:3][CH:4]=1
Reactant: CCN(C)c1nc(Cl)ncc1Cl
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)c1nc(Oc2cc(C)c([N+](=O)[O-])cc2C)ncc1Cl

Procedure:
A solution of 16.8 g (40 mmol) 2,5-dichloro-N-ethyl-N-methylpyrimidin-4-amine, 7.35 g 4-nitro-2,5-dimethylphenol (44 mmol) and 8.29 g potassium carbonate (60 mmol) in 70 ml DMF were stirred for 20 hrs at 100° C. After adding the mixture to 150 ml water the resulting suspension was extracted twice with 50 ml dichloromethane. The combined organic layers were washed with aqueous solution of sodium hydroxide. The organic layer was dried over magnesium sulfate, concentrated in vacuo and column chromatography (dichloromethane) yielded 8.3 g (47%) with a purity of 76%; log P (pH=2.3)=4.07.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl.N([O-])=O.[Na+].[I-:16].[K+]>O>[I:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Ic1ccc2[nH]ncc2c1
Temperature: -5 °C
Yield: 75.4 %

Procedure:
5-Amino-1H-indazole (10.21 g, 76.7 mmol) was suspended in a mixture of water (100 mL), ice (100 mL), and concentrated HCl (35 mL). The mixture was cooled in an ice-salt bath to an internal temperature of −5° C. To this mixture was added a solution of sodium nitrite (5.82 g, 84.4 mmol) in water (30 mL), which had been cooled to 0° C. The resulting diazonium solution was stirred for 10 minutes at −5° C., then a solution of potassium iodide (15.3 g, 92 mmol) in water (50 mL) was added slowly dropwise. Significant foaming occurred with the first few drops of KI solution, and then a black, tarry gum formed. After the addition was completed, the mixture was heated to 90° C. for 1 hour. The tarry precipitate dissolved and purple vapor was evolved during heating. The reaction was then cooled to room temperature, causing a fine brown precipitate to form. This precipitate was collected by suction filtration, and dried under vacuum to give 5-iodoindazole 2a (14.12 g, 75%) as a brown powder: Rf=0.28 (50% ethyl acetate/hexanes); 1H NMR (DMSO-d6) δ 7.40 (d, 1H, J=9.0 Hz), 7.56 (dd, 1H, J=8.5, 1.5 Hz), 8.01 (s, 1H) 8.16 (s, 1H), 13.23 (s, 1H). Anal. (C7H5IN2) C, H, I, N.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=3[CH:10]=2)O1.Br[C:40]1[C:45]2=[N:46][S:47][N:48]=[C:44]2[C:43](Br)=[CH:42][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH2:30]([C:12]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:11]2[CH:10]=[C:9]([C:40]3[C:45]4=[N:46][S:47][N:48]=[C:44]4[C:43]([C:9]4[CH:21]=[CH:20][C:19]5[C:18]6[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=6)[C:12]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=5[CH:10]=4)=[CH:42][CH:41]=3)[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: Brc1ccc(Br)c2nsnc12
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(-c3ccc(-c4ccc5c(c4)C(CCCCCCCC)(CCCCCCCC)c4ccccc4-5)c4nsnc34)cc21
Temperature: 80 °C
Yield: 64.4 %

Procedure:
Into a flask was introduced 100 mL of toluene, 8.77 g of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,9-dioctylfluorene (10) (17 mmol), 2 g of 4,7-dibromo-benzo[1,2,5]thiadiazole (5) (6.8 mmole), 0.69 g of Aliquat® 336 (1.7 mmol) and 17.2 mL of aqueous 2M Na2CO3. This was N2 purged for 1 h. The flask was heated to about 80° C. and 33 mg of tetrakistriphenylphosphine palladium (0) (0.0042 mmol) then added under a nitrogen purge. The content of the flask was refluxed for 3 days. The reaction flask was allowed to cool to RT and about 50 mL water added and the organic layer separated. The aqueous layer was extracted with 50 mL toluene. The organic layers were combined and washed successively with water twice and then dried over MgSO4. Concentration gave an oil which was purified by flash chromatography (eluent: 10% CH2Cl2 in Hexane) to give 4.0 g (64% yield) of 4,7-Bis-(9,9-dioctyl-9H-fluoren-2-yl)-benzo[1,2,5]thiadiazole 16 as a green solid. Compound 16 was shown to exhibit a blue-white fluorescence (425 nm and 518 nm emissions) in dilute toluene solution when excited at 375 nm. At 0.2 mg/mL or as a spin cast thin film, this compound gave a green fluorescence (518 nm) under UV excitation.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:11].[OH-].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH:1]1([CH2:7][C:8]([NH2:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)CC1CCCCC1
Yield: 52.2 %

Procedure:
Cyclohexylacetyl chloride (1 mL, 6.52 mmol) was added to solution of NH4OH (˜15M, 5 mL, ˜75 mmol) in EtOAc (5 mL) and satd. NaHCO3 (5 mL) and stirred at RT for 20 minutes. The layers were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 2-cyclohexylacetamide (481 mg, 52%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[OH:16])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH2:24][CH2:25][CH2:26][CH:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:28])[N:3]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2O)n1
Reactant: CC(CCCBr)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a stirred solution of 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.1 g, 5.00 mmol), cesium carbonate (2.44 g, 7.49 mmol) in DMF (20 mL) was added tert-butyl (5-bromopentan-2-yl)carbamate (2.45 g, 9.25 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h while monitoring by TLC and LC-MS. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (250 mL) and washed with brine (2×100 mL). The organic layer was concentrated under reduced pressure and was purified by flash chromatography using a Teledyne ISCO instrument (40 g silica column, 2-3% of methanol in chloroform) to give tert-butyl (5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)carbamate (1.5 g, 74.1%) as a light brown solid. LC-MS (M+H)+=406.2. 1H NMR: (400 MHz, CDCl3) δ ppm 8.86 (1H, s), 8.09-8.07 (1H, d, J=8.8 Hz), 7.99-7.93 (2H, m), 4.33 (1H, br s), 4.27-4.24 (2H, t, J=6.4 Hz), 3.73 (1H, br s), 2.50 (3H, s), 1.98-1.95 (2H, m), 1.61-1.57 (2H, m), 1.44 (9H, s), 1.17-1.15 (3H, d, J=8 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:24]([NH:26][NH2:27])=O>O=P(Cl)(Cl)Cl>[N:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:24]=[N:26][N:27]=[C:7]2[C:6]2[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Nc2ccncc2)cc1
Reactant: NNC=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of 4-Methoxy-N-pyridin-4-yl-benzamide (75 mg) in POCl3 (3 ml) was added PCl5 (68 mg) and the reaction mixture heated at reflux for 5 h. The reaction mixture was concentrated and dissolved in dimethyl formamide (2 ml) and Formic acid hydrazide (5 eq, 100 mg) was added and stirred for 2 h. The reaction mixture was concentrated and diluted with isopropanol (3 mL) and 0.25 ml of conc. HCl was added. The reaction mixture stirred for 18 h, quenched with 1 NaOH, extracted with dichloromethane, dried magnesium sulfate and concentrated. The crude product dissolved in methylene chloride (2 mL) and boron tribromide (0.63 mL 1.0M hexanes) was added at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with 1 N NaOH and pH adjusted to 9, extracted with dichloromethane, dried magnesium sulfate, filtered and concentrated. Purification via Biotage MPLC chromatography eluting with 0-20% methanol/methylene chloride provided the title compound (32 mg, 55%). MS: (M+H m/z=239.2).
Reaction SMILES: C(S(O)(=O)=O)CCC.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][CH3:29])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[NH2:30][CH2:31][C@H:32]([OH:47])[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]2[C:36]=1[CH2:37][CH2:38][C:39](=[O:46])[NH:40]2>>[OH:47][C@H:32]([CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]2[C:36]=1[CH2:37][CH2:38][C:39](=[O:46])[NH:40]2)[CH2:31][NH:30][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][CH3:29])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Agent: CCCCS(=O)(=O)O
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid ]4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3H), 1.20-1.40 (m, 4H), 1.50-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.39 (t, J=7.3 Hz, 2H), 2.50-2.80 (m, 5H), 2.85 (t, J=7.3 Hz, 2H), 2.85-3.00 (m, 2H), 3.45-3.60 (m, 2H), 3.75-3.85 (m, 3H), 6.44 (d, J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 8.74 (s, 1H); MS (ES) m/z: 546.9 (MH+); HRMS Calcd. for C27H39N4O6S(MH+): 547.2590. Found: 547.2583.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:8]1[CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][C:7]1=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[C@H]1CNC(=O)C1
Reactant: BrCCCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H]1CC(=O)N(CCCCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of (R)-4-butylpyrrolidin-2-one (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of (R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one as a colorless oil: 1H NMR (CDCl3) δ 7.33 (m, 5 H), 4.51 (s, 2 H), 3.45 (m, 3 H), 3.27 (t, 2 H), 2.99 (dd, 1 H), 2.52 (dd, 1 H), 2.32 (m, 1 H), 2.06 (m, 1 H), 1.24-1.71 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e 318 [M+H]+.