Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[CH2:23]([Si:26](OC)([O:29][CH3:30])[O:27][CH3:28])[CH2:24][CH3:25]>C(O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Si:26]([CH2:23][CH2:24][CH3:25])([O:29][CH3:30])[O:27][CH3:28]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: CCC[Si](OC)(OC)OC
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Product: CCC[Si](OC)(OC)c1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A 500 mL round bottomed flask was charged with hexane (200 mL, Aldrich) and bromo-2,4-dimethoxybenzene (12.2 g, 56.0 mmol, Aldrich). The contents were cooled to 0° C. and n-butyl lithium (34.7 mL of a 1.6M solution in hexanes, 55.5 mmol, Aldrich) was added over 15 minutes (white precipitate). The contents were stirred at room temperature for ninety (90) minutes. The solution was added, via cannula, into a 1000 mL round bottomed flask containing hexane (300 mL, Aldrich) and propyl-trimethoxysilane (9.8 mL, 56 mmol). The reaction was stirred at room temperature overnight (18 hours). Ethanol (10 mL, Aldrich) was added to quench residual base. The contents were poured into 0.2N HCl (250 mL). The layers were separated and the product extracted into ether (2×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (16.2 g crude). Distillation under reduced pressure (b.p. 115° C., 0.04 mm Hg) provided 2,4-dimethoxyphenyl-propyl-dimethoxysilane (9.13 g, 33.8 mmol, 61% yield); C13H22O4Si (Mw=270.40); 1H NMR (CDCl3) δ 7.5 (d, 1H), 6.5 (m, 1H), 6.4 (d, 1H), 3.8 (s, 3H), 3.8 (s, 3H), 3.5 (s, 6H), 1.4 (m, 2H), 0.9 (t, 3H), 0.8 (t, 2H); 13C NMR (CDCl3) δ 165.8, 163.2, 137.6, 112.7, 104.6, 97.5, 55.0, 54.9, 50.4, 17.7, 16.2, 15.4; IR (capillary film) ν 2950, 2836, 1596, 1571, 1460, 1299, 1206, 1154, 1089, 1036; MS m/z (relative abundance) 270 (11.1), 227 (45.6), 197 (100), 167 (24.4), 137 (10.9), 121 (22.6), 91 (9.9), 59 (18.4).
Reaction SMILES: [CH2:1]([N:5]1[C:12](S(C)=O)=[C:11]([CH:16]([CH3:18])[CH3:17])[C:9](=[O:10])[NH:8][C:6]1=[S:7])[CH2:2][CH2:3][CH3:4].[CH3:19][C:20]1[CH:21]=[C:22]([SeH:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1.C1([SeH])C=CC=CC=1>>[CH2:1]([N:5]1[C:12]([Se:27][C:22]2[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:19])[CH:21]=2)=[C:11]([CH:16]([CH3:18])[CH3:17])[C:9](=[O:10])[NH:8][C:6]1=[S:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(S(C)=O)c(C(C)C)c(=O)[nH]c1=S
Reactant: Cc1cc(C)cc([SeH])c1
Agent: [SeH]c1ccccc1
Product: CCCCn1c([Se]c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=S
Yield: 88 %

Procedure:
The titled compound was prepared in the same manner as described in Example 39 by using 1-butyl-5-isopropyl-6-(methylsulfinyl)-2-thiouracil and (3,5-dimethylphenyl) selenol in place of 1-(4-acetoxybutyl)-5-ethyl-6-(methylsulfinyl)-2-thiouracil and benzeneselenol, respectively.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Cl)n1
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2cccnc2)n1

Procedure:
By carrying out the operation analogously to example 41, starting from 6-chloro-2-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XIII, and 3-pyridineboronic acid, the desired product is obtained in the form of a cream powder (yield=38%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:9]=[CH:10][C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[CH:10]=[N:9]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1cnn2C1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.1 %

Procedure:
To the solution of tert-butyl 3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (700 mg, 2.2 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The resulting mixture was stirred at rt for 1 h, and concentrated in vacuo to afford the title compound (620 mg, 100%) which was used without further purification. ESI-MS (M+H′): 219.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].[C:8](#N)[CH3:9]>[Ni]>[CH3:8][CH:9]1[NH:7][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][NH:1]1
Reactant: CC#N
Reactant: CCC(N)CCN
Agent: [Ni]
Product: CCC1CCNC(C)N1
Temperature: 90 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Ninety grams (96.8% purity, 0.854 mole) 1,3-diaminopentane, 60 g acetonitrile (1.46 moles) and 3 g powdered nickel on alumina catalyst were charged to a 300 ml autoclave described in Example 1. The mixture was stirred and heated at 90° C. and 650 psig pressure for 6 hours followed by cooling to 25° C. Analysis of the filtered product on a capillary GC column showed a 42.9% conversion of 1,3-diaminopentane and 94% yield of 2-methyl-4-ethylhexahydropyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C@@H:10]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C@@H:11]3[N:12](C(OC(C)(C)C)=O)[C:13]=2[CH:14]=[CH:15][CH:16]=1.[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C@@H:10]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C@@H:11]3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2c3c(-c4ccccc4F)cccc3N(C(=O)OC(C)(C)C)[C@H]2CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Reaction time: 26.5 h
Yield: 72 %

Procedure:
(5aS*,10bS*)-Di(tert-butyl) 10-(2-fluorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.094 g, 0.19 mmol) was dissolved in a 4.0 N solution of HCl in dioxane (4 mL) and stirred at room temperature for 26.5 hours. After the reaction mixture was concentrated in vacuo CH3OH was added and the solution was concentrated in vacuo and recrystallized from CH3OH/EtOAc to give 0.054 g (72%) of a white solid as the title compound: mp 248.0-256.7° C. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (m, 1 H), 9.05 (m, 1H), 7.51-7.43 (m, 2H), 7.36-7.29 (m, 3 H), 7.03-6.98 (m, 2H) 4.34-4.33 (m, 1H), 3.85 (m, 1H), 3.29 (m, 1H), 3.06 (m, 1H), 2.90 (m, 1H), 2.69-2.67 (m, 1H), 2.27 (m, 2H), 1.67 (m, 1H), 1.36-1.34 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.8, 157.3, 132.7, 130.8, 130.7, 130.2, 130.1, 128.6, 126.4, 126.2, 124.8, 124.7, 115.9, 115.7, 59.7, 44.8, 43.9, 41.7, 26.5, 25.7; IR (diffuse reflectance) 2954 (s), 2847 (s), 2817 (s, b), 2755 (s), 2726 (s, b), 2668 (s, b), 2651 (s, b), 2572 (s, b), 2538 (s), 2469 (s), 2350, 2342, 1738, 1474, 771 cm−1; HRMS (FAB) calcd for C18H19FN2+H1: 283.1610 found 283.1612.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:47])C=1>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-:47])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc[n+]([O-])c3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(pyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (1.15 g, 2.127 mmol) in DCM (22 mL) was cooled to 0° C. and m-CPBA (0.953 g, 4.25 mmol) was added. The reaction was warmed to room temperature. After 2 hours the reaction was quenched with aqueous sodium bisulfite (20 mL). The reaction was then diluted with EtOAc (150 mL) and washed vigorously with aqueous sodium bisulfite (3×40 mL). The organics were washed with brine (2×40 mL), saturated aqueous NaHCO3 (3×40 mL) and then brine (2×40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (1.18 g, 100%). LC-MS=557.2 (M+1)+.
Reaction SMILES: [N+](C1C=C([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])C=CC=1N)([O-])=O.[N+:21]([C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][C:29]=1[NH2:30])([O-:23])=[O:22].C(N(CC)CC)C>CC(C)=O>[N+:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=1[NH:30][O:11][S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])([O-:23])=[O:22]
Reactant: Nc1ccc(OS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NOS(=O)(=O)c1ccccc1

Procedure:
In order to prepare 2-nitro-4-phenylsulfonyloxy-aniline, 15.4 g of 3-nitro-4-amino-phenol in 100 ml of acetone were mixed with 14 ml of triethylamine, and 17.6 g of benzane-sulfonic acid-chloride dissolved in 30 ml of acetone were added dropwise, while stirring, at an internal temperature not exceeding 20° C in an ice bath. The mixture was continued to be stirred for another 3 hours at room temperature, the triethylamine-hydrochloride was filtered off, and the filtrate was evaporated to dryness. The residue was then stirred with 50 ml of methanol and was filtered. After washing with methanol and drying, 18.2 g of 2-nitro-phenylsulfonyloxy-aniline were obtained, which has a melting point of 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 542.3 [(M+H)+]; mp 207-208° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18]C(=O)OC(C)(C)C)[CH:16]=2)[NH:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=2)[C:31]=1[F:47])=[O:27]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:31]=1[F:47])=[O:27])=[C:9]2[Cl:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Cl)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(N)cc4c3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl (3-chloro-2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (0.030 g, 0.050 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.021 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.98-12.29 (m, 1H), 8.80-9.68 (m, 2H), 8.53-8.63 (m, 1H), 7.78-7.85 (m, 1H), 7.39-7.57 (m, 5H), 7.31-7.39 (m, 1H), 7.09-7.20 (m, 1H), 4.41-4.89 (m, 2H). ES MS: m/z 503 (M+1).
Reaction SMILES: [CH2:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:13]1[S:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=1
Reactant: CCCCCCCCCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1ccc(Br)s1
Temperature: 100 °C
Yield: 94 %

Procedure:
2-Decylthiophene (52.8 g, 0.235 mol) prepared above and DMF (200 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. A solution of N-bromosuccinimide (hereinafter referred to as “NBS”) (44.0 g, 0.247 mol) in DMF (100 ml) was added dropwise to the solution at room temperature in an argon gas stream over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred with heating at 100° C. for about 2 hr. After the completion of the reaction, water (300 ml) was added to the reaction solution, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (n-hexane) to give an objective compound 2-bromo-5-decylthiophene as a yellow liquid (67.0 g, yield 94.0%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.61 (m, 2H), 2.73 (t, 2H, J=7.32 Hz), 6.52 (d, 1H, J=3.90 Hz). 6.83 (d, 1H, J=3.90 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.F[B-](F)(F)F.[H+].[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][C:7]1[C:2]([F:1])=[CH:3][C:4]([O:21][CH3:22])=[C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:6]=1
Reactant: COc1cc(F)ccc1-c1cnc2nc(C(C)(C)O)cnn12
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: COc1cc(F)c(Br)cc1-c1cnc2nc(C(C)(C)O)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (−20° C.) solution of 2-[7-(4-fluoro-2-methoxyphenyl)imidazo[1,2-b][1,2,4]triazin-3-yl]propan-2-ol (0.4 g, 1.32 mmol) in acetonitrile (4 ml) under nitrogen was added tetrafluoroboric acid (54 wt % solution in Et2O, 0.21 ml, 1.59 mmol) and then N-bromosuccinimide (0.28 g, 1.59 mmol) slowly such that the internal temperature remained less than −10° C. After addition the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring at this temperature continued for 16 h. A 40% aqueous solution of NaHSO3 (10 ml) was added and the reaction mixture extracted with EtOAc (3×50 ml). Organic extracts were washed with water (50 ml), saturated aqueous brine (50 ml), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc) to give a quantitative yield of the title compound: 1H NMR (400 MHz, CDCl3) δ 1.71 (6H, s), 3.47 (1H, s), 3.89 (3H, s), 6.86 (1H, d, J 10.3), 8.21 (1H, d, J 7.9), 8.29 (1H, s), 8.74 (1H, s); MS (ES+) m/z 381, 383 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:19]1([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH:18]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:21]=[CH:20]1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example B14, 102.8 mg of 4-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[C:15]1[N:20]=[CH:19][C:18]([C:21](O)([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[C:17]([O:29][CH3:30])[CH:16]=1)[CH3:6]>N1C=CC=CC=1>[CH2:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:5][CH3:6])[C:8]=1[C:15]1[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]([CH2:25][CH2:26][CH3:27])=[CH:22][CH2:23][CH3:24])=[CH:19][N:20]=1)[CH3:14]
Reactant: CCCC(O)(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC=C(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
SOCl2 (0.5 mL) is added to a solution of 4-[6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-heptan-4-ol in anhydrous pyridine (5 mL) at 0° C. under nitrogen. The resulting mixture is stirred at room temperature overnight. The volatile materials are removed in vacuo. The residue is treated with water (5 mL), aqueous Na2CO3 (5 mL), and ether. The organic layer is separated and the aqueous is extracted with ether (2×10 mL). The combined extract is washed with brine, dried, and concentrated in vacuo. The crude is purified by PTLC (8:1 hexane/EtOAc) to give 2-(2,6-diethyl-phenyl)-4-methoxy-5-(1-propyl-but-1-enyl)-pyridine. 1H NMR (CDCl3) 8.26 (s, 1H), 7.29 (t, 1H), 7.16 (d, 2H), 6.72 (s, 1H), 5.55 (t, 1H), 3.82 (s, 3H), 2.22-2.37 (m, 8H), 1.30 (m, 2H), 0.87-1.10 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18](N)=[O:19].C(=O)(O)[O-:22].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:19])=[O:22]
Reactant: NC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 90 °C
Yield: 35 %

Procedure:
A stirred suspension of compound (xv) in conc. sulfuric acid (5 mL) and water (5 mL) were heated to 90° C. After 2 h the reaction mixture was diluted with water, neutralized with sodium bicarbonate and extracted with EtOAc (3×15 mL). The organic layer was dried (Na2SO4) and concentrated to give 6-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxylic acid (xvi) (70 mg, 35%) as a white solid. ESI-MS m/z calculated for [M+H]+: 336.98; found: 336.80.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=2)[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nn1nc(Cc2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cc2ccccc2)c2ccccc2c1=O

Procedure:
The product of Example 139A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66-11.72 (bs, 1H), 8.32 (dd, J=7.8, 1.5 Hz, 1H), 7.97-8.00 (m, 1H), 7.92 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.86 (ddd, J=7.8, 7.1, 1.3 Hz, 1H), 7.24-7.37 (m, 4H), 7.11-7.23 (m, 4H), 4.32-4.32 (bs, 2H), 3.77 (s, 2H); LC/MS (APCI) M/Z 406 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[CH2:15]
Reactant: N#Cc1ccc2nccc(Br)c2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc2ccc(C#N)cc12
Yield: 64.5 %

Procedure:
To a solution of (c) (1 g, 4.3 mmol) and vinyltributyltin (1.5 mL, 5.17 mmol) in degassed toluene (20 ml) was added tetrakis(triphenylphosphine) palladium (0) (245 mg, 5 mol %) and the mixture was refluxed under argon for 2 hours. Evaporation and flash silica chromatography eluting with chloroform afforded the product as a pale yellow solid (500 mg, 64%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][CH:70]=[C:71]([Cl:73])[CH:72]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:73][C:71]1[CH:72]=[C:67]([C:57]2[C:56]([CH3:74])=[C:55]([NH:47][C:46]3[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[N:42][CH:43]=[C:44]([N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[CH:45]=3)[C:64]3[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=3[F:65])[N:58]=2)[CH:68]=[N:69][CH:70]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cncc(Cl)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(Cl)c2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.049 mmol), 2,5-dimorpholinopyridin-3-amine (0.098 g, 0.37 mmol), 4-chloro-2-(5-chloropyridin-3-yl)-5,7-difluoro-3-methylquinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.074 g, 0.77 mmol) in toluene (3.1 mL) at 120° C. for 3.2 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(5-chloropyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.71 (2H, dd, J=11.5, 2.2 Hz), 8.00 (1H, t, J=2.2 Hz), 7.79 (1H, d, J=11.0 Hz), 7.68 (1H, d, J=2.7 Hz), 7.61 (1H, d, J=9.4 Hz), 7.05 (1H, ddd, J=13.1, 8.4, 2.4 Hz.), 6.36 (1H, br. s.), 3.91 (4H, br. s.), 3.83 (4H, app t, J=4.7 Hz), 3.22 (4H, br. s), 3.05 (4H, app t, J=4.9 Hz), 2.18 (3H, s). Mass Spectrum (ESI) m/e=553.2 (M+1).