Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1CCOC1CCCCO1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CCOCC>[CH3:9][C:5]1([CH3:10])[CH:6]2[CH2:8][CH:4]1[CH2:3][CH2:2][CH2:7]2
Reactant: CC1(C)[C@H]2C[C@H](O)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)C2CCCC1C2
Reaction time: 0.25 h
Yield: 265.9 %

Procedure:
To a solution of 13 g of (1S,2S,3S,5R)-3-hydroxy-6,6-dimethyl-2-[2-(tetrahydropyran-2-yloxy)-ethyl]bicyclo[3.1.1]heptane 14 [Jap. Unexamined Pat. Pub. No. 13551/1983] in 130 ml of dichloromethane is added 9.9 ml of triethylamine in a stream of nitrogen and then 6.16 g of methanesulfonyl chloride is dropwise added at -20° C., and the resulting mixture is stirred at the same temperature for 15 minutes. The reaction mixture is diluted with ether, washed with water, a saturated aqueous solution of ammonium chloride and a saturated sodium chloride aqueous solution successively, dried over sodium sulfate, and evaporated under reduced pressure to give 16 g of the titled compound 14a, of which the physical constant is as follows.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 5.5 h
Yield: 89.5 %

Procedure:
The above general procedure was followed using 4-chlorobenzonitrile (138 mg, 1.00 mmol) and diphenylamine (169 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 2.0 mL of toluene. After 5.5 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 50% toluene/hexanes to give 242 mg (90%) of N-(4-cyanophenyl)diphenylamine as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(O)C.O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:30][CH2:27][CH:28]=[CH2:29])[CH:3]=1)=[O:15]
Reactant: C=CCN
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O
Solvent: CCO
Product: C=CCNc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 140 °C

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.669 mmol) was suspended in ethanol (4 mL) followed by addition of allylamine (0.753 mL, 10.03 mmol). The sealed contents were heated (heat block) at 140° C. for ca. 60 h, and then allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and then filtered. The collected solid was washed with additional water and then dried in vacuum oven at 45° C. for 18 h. The final product was isolated as an off-white solid, 0.225 g (83%). LCMS E-S (M+H)=394.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.00 (t, J=5.43 Hz, 2H), 4.32 (d, J=5.05 Hz, 2H), 4.94 (quin, J=6.69 Hz, 1H), 5.09 (dd, J=10.36, 1.77 Hz, 1H), 5.18-5.29 (m, 1H), 5.85-6.01 (m, 2H), 6.68 (s, 1H), 7.37 (t, J=5.56 Hz, 1H), 7.84 (s, 1H), 8.45 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:26])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:19](=[C:18]2/[C:17](=[O:26])[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:34][CH:33]=3)[C:27]3[C:32]/2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: COc1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Product: COc1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-phenyl-propynoic acid (4-methoxy-benzyl)-phenylamide. 1H NMR (300 Hz, CDCl3): δppm 3.77 (s, 3H), 4.88 (s, 2H), 6.53 (d, 1H), 6.67-6.71 (m, 2H), 6.80 (dd, 1H), 6.85-6.90 (m, 2H), 7.07 (t, 1H), 7.19-7.43 (m, 10H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[C:17]([Cl:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[ClH:25].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH:15][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CN1CCC(Oc2cccc(NC(=O)c3ccncc3)n2)CC1
Yield: 89.1 %

Procedure:
Using a method similar to example 160 using 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 150 mg, 0.724 mmol) and isonicotinoyl chloride hydrochloride (192 mg, 1.08 mmol) yields the title compound (225 mg, 89%). Mass spectrum (ion spray): m/z 313.1 (M+1); Analysis calculated for C17H21N4O2Cl.0.2H2O. Theory: C, 57.93; H, 6.12; N, 15.90. Found: C, 57.78; H, 6.28; N, 15.88. mp=254-256° C.
Reaction SMILES: [CH2:1](OC(C)(C)CCCC(C)CC=CC(=O)C)C.[CH2:18]([O:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:36])[CH2:26][CH:27]=[CH:28][C:29]([CH3:35])=[CH:30][C:31]([O:33][CH3:34])=[O:32])[CH3:19].C(CP(=O)(OCC)OCC)(OCC)=O>>[CH2:18]([O:20][C:21]([CH3:37])([CH3:38])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:36])[CH2:26][CH:27]=[CH:28][C:29]([CH3:35])=[CH:30][C:31]([O:33][CH2:34][CH3:1])=[O:32])[CH3:19]
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=O
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC
Agent: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)OCC

Procedure:
Following the process of Example 13, 10-ethoxy-6,10-dimethylundec-3-en-2-one is converted into methyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate. Reaction of 10-ethoxy-6,10-dimethylundec-3-en-2-one with the carbanion of diethyl carboethoxymethylphosphonate yields ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>C(OCC)(=O)C.CN(C)C1C=CN=CC=1.[Pd]>[NH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:3][C:2]=1[CH3:1])[C:26]([CH3:27])=[O:28]
Reactant: Cc1cc(-c2ccccc2C#N)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1C
Reaction time: 1 h
Yield: 51 %

Procedure:
2-(3-Methyl-4-nitrophenyl)benzonitrile (6.3 moles, 1.5 g) was hydrogenated in ethyl acetate (50 ml) over 5% Pd/C (0.50 g). The catalyst was filtered, and the solution concentrated to an oil. The oil was dissolved in 10 ml of methylene chloride and triethylamine (9.4 mmoles, 1.4 ml). Acetic anhydride (9.4 mmoles, 0.960 g) and 4-dimethylaminopyridine (50 mg) were added. The reaction was stirred for 1 hour and poured into 20 ml of 5N HCl. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The product was crystallized from ether and hexane to yield 1.2 g of 2-(4-acetamino-3methylphenyl)benzonitrile. (MS)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1.[NH4+].[Cl-]>[CH2:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCOc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.3 %

Procedure:
A solution of 4-Bromo-2-methyl-phenol (2.0 g, 10.7 mmol) in THF (100 mL) was added solid Cs2CO3 (3.8 g, 11.7 mmol) and allyl bromide (1.9 mL, 21.4 mmol). The reaction mixture was stirred at room temperature for 20 hours. Upon completion, the solution was diluted with aqueous NH4Cl and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography (0 to 100% ethyl acetate in hexanes) to provide 1.1 g (45%) of a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16]>C(OCC)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH3:13])=[S:11])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(N=C=S)cc1
Reactant: CC(C)(C)CN
Solvent: CCOCC
Product: CN(C)c1ccc(NC(=S)NCC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 4-dimethylaminophenyl isothiocyanate (4.5 g, 25 mmol) in diethyl ether (100 mL) at room temperature was added a solution of 2,2-dimethyl-1-propanamine (2.94 mL, 25 mmol) and the reaction was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to afford 5.7 g (85%) of N-[4-(dimethylamino)phenyl]-N′-(2,2-dimethylpropyl)-thiourea, as a white solid: mp 174–176° C.; 1H NMR (DMSO-d6): δ 9.17 (br s, 1H), 7.13 (d, 2H), 7.10 (br s, 1H), 6.68 (d, 2H), 3.33 (d, 2H), 2.86 (s, 6H), and 0.87 ppm (s, 9H); IR (KBr) 3400, 3160, 1600, 1550 cm−1; MS (m/z) 265 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.[C:15]([O-:18])([O-])=[O:16].[Na+].[Na+].BrBr>[Fe].C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:3]#[C:4][C:13]3[CH:8]=[CH:9][C:10]([C:15]([OH:18])=[O:16])=[CH:11][CH:12]=3)[CH:12]=2)[O:7][CH2:6][CH2:5]1
Reactant: COCC1(C)CCOc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Fe]
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Product: COCC1(C)CCOc2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 0 °C
Reaction time: 0.6 h
Yield: 95 %

Procedure:
2.00 g (10.4 mmol) of 4-methoxymethyl-4-methyl-chroman was dissolved in 25 ml of abs. CH2Cl2 and treated with a catalytic amount of Fe-powder and Na2CO3. After cooling to 0° C., 1.21 m of bromine (1.1 eq.) was added and the mixture kept for 0.6 h at this temperature. Pouring onto crushed ice, extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, filtration and evaporation of the solvents, and ensuing flash chromatography over SiO2 (hexane/ethylacetate 95/5) yielded 1.676 g of pure title compound as colorless oil (GC>95%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.[CH3:34][C:35]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=1)([CH2:45][CH3:46])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:34][C:35]([C:47]1[CH:48]=[CH:49][CH:50]=[C:51]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([C:15]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:9]=[C:10]([C:11]([F:12])([F:14])[F:13])[C:3]=23)[CH:52]=1)([CH2:45][CH3:46])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43]
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
4-iodo-3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridine (135 mg, 0.2431 mmol) and tert-butyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (94.65 mg, 0.2431 mmol) were dissolved in dry Dioxane (1 mL) and Na2CO3 (364.6 μL of 2 M, 0.7293 mmol) was added. The solution was degassed (vacuum/nitrogen cycles×5), Pd[P(tBu)3]2 (12.42 mg, 0.02431 mmol) was added and stirred at 60° C. overnight. The reaction was allowed to cool to RT and partitioned between EtOAc and saturated Na2CO3. The aqueous layer was extracted with further EtOAc (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a dark purple solid. The resulting solid was purified by column chromatography (15% EtOAc in hexanes, ˜75 mL silica) to give a slightly brown gum (164.7 mg, 98% Yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH: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)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>O1CCCC1.C(OCC)(=O)C>[Br:34][CH2:35][C:36]([N:9]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]1)[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:8][CH:7]=1)=[O:37]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)CBr)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of the product of Example 166A (480 mg, 1.39 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.486 mL, 2.79 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled in an ice water bath for 10 minutes followed by the dropwise addition of bromoacetyl bromide (0.146 mL, 1.67 mmol) via syringe. The reaction was stirred for 30 minutes at 0° C., then 1 hour at ambient temperature and 3 hours at reflux. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was washed with 1 N aqueous HCl and saturated NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF25-60 g column; 50% ethyl acetate/hexanes) which yielded the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.74 (d, J=8.4, 2H), 7.34 (d, J=8.2, 2H), 4.80-4.66 (m, 1H), 4.25-4.04 (m, 2H), 3.49 (s, 2H), 2.79 (t, J=12.4, 2H), 1.87-1.77 (m, 2H), 1.39 (s, 9H), 1.29-1.11 (m, 2H); MS (DCI+) m/z 482/484 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][N:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18]([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:6]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a mixture of 4-methoxy-7-azaindole (6.4 g, 43.2 mmol) in dichloromethane (200 mL) and 50% aqueous sodium hydroxide (200 mL) was added benzenesulfonyl chloride (6.1 mL, 47.5 mmol) and tetrabutylammonium bromide (1.4 g, 4.3 mmol). The mixture was stirred vigorously at room temperature for 18 hours. The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was recrystallized from ethyl acetate and hexanes to give 9.2 g of 1-benzenesulfonyl-4-methoxy-7-azaindole as a yellow solid. 1H NMR (DMSO-d6) δ 8.30 (d, J=5 Hz, 1H), 8.18 (d, 1 Hz, 1H), 7.58 (m, 2H), 7.47 (m, 2H), 6.67 (d, 4 Hz, 1H), 6.61 (d, 4 Hz, 1H), 3.94 (s, 3H). MS (m/z) 289 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH2:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19]>>[CH2:18]([N:20]1[C:24]([NH:25][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[CH:23][CH:22]=[N:21]1)[CH3:19]
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: CCn1nccc1N
Product: CCn1nccc1NC(=O)c1ccc(OC)c2oc(COC)cc12
Yield: 16.7 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.15 g) and 2-ethyl-2H-pyrazol-3-ylamine (85 mg). Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane increasing to ethyl acetate afforded the title compound as a yellow solid (35 mg).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][CH2:13]C(O[Si](C)(C)C)(C#N)[C:11]=2[CH:23]=1.[C:24]([OH:27])(=[O:26])[CH3:25]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:15][CH2:14][CH2:13][CH:25]([C:24]([OH:27])=[O:26])[C:11]=2[CH:23]=1
Reactant: C[Si](C)(C)OC1(C#N)CCSc2ccc(Cl)cc21
Reactant: CC(=O)O
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1CCSc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of tin(II) chloride dihydrate (115.42 g, 0.51 mol) and 6-chloro-3,4-dihydro-4-(trimethylsiloxy)-2H-1-benzothiopyran-4-carbonitrile (37.53 g, 0.126 mol) in 1:1 acetic acid/concentrated hydrochloric acid is heated at reflux under nitrogen for 3 days, cooled to room temperature and diluted with chloroform. The aqueous phase is separated and extracted with chloroform. The organic phase and organic extracts are combined and extracted with 2N sodium hydroxide solution. The combined aqueous extracts are washed with chloroform and acidified to pH 3. The acidic aqueous mixture is extracted with chloroform and the combined organic extracts are dried and concentrated in vacuo to obtain a residue. The residue is triturated with an ether/petroleum ether mixture and filtered to give the title product as an off-white solid (12.56 g, mp 139°-150° C.).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:2]=12.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=3)[CH:8]=[CH:9][C:2]=12
Reactant: CNc1ccc(-c2ccc3nonc3c2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CNc1ccc(-c2ccc3nonc3c2)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
140 mg (0.62 mmol) (4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-methyl-amine are stirred at 0° C. in 2 mL concentrated sulfuric acid, then treated with 66 mg (1.05 eq.) potassium nitrate and stirred an additional 4 hours. The reaction mixture is poured onto ice, the precipitate filtered off, thoroughly washed with water and dried under high vacuum. The crude product is column chromatographed with ethyl acetate/petroleum ether 1:2 to yield after evaporation of the product-containing fraction the desired product as an orange solid. MS(ES−): 269 (M−1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1F>CS(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[N:10]1[CH:11]=[CH:12][C:8]([CH3:7])=[N:9]1
Reactant: Fc1cc(Br)ccc1Br
Reactant: Cc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccn(-c2cc(Br)ccc2Br)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Potassium t-butoxide (16.3 g, 145 mmol) was dissolved in DMSO (100 mL). To this solution was added 3-methylpyrazole (10.4 g, 120 mmol) and the reaction was heated at 50° C. for 30 min. 1,4-Dibromo-2-fluorobenzene (31 g, 120 mmol) was then added and the reaction stirred at 50° C. for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, dried over Na2SO4, and then filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(2,5-dibromophenyl)-3-methyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)=[CH:6][C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: COCCOc1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 100 °C
Yield: 23.9 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.06 g, 4.95 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.508 g, 3.51 mmol), Am-Phos (Aldrich, 0.125 g, 0.176 mmol) and potassium acetate (Aldrich, 1.04 g, 10.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and 10% IPA in CHCl3 (3×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with DCM and the resulting solid was collected to afford 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.234 g) as an off-white solid. The filtrate was concentrated and purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 12.5%) to afford additional material (0.399 g) as a pale yellow solid. Total yield was 0.632 g, 64%. 1H NMR (400 MHz,CDCl3) δ ppm 8.14 (dd, J=7.63, 3.13 Hz, 1H) 8.01 (dd, J=2.93, 1.76 Hz, 1H) 5.56 (br. s., 2H) 4.19-4.27 (m, 2H) 3.75-3.81 (m, 2H) 3.46 (s, 3H) 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:35])[C:16]2[O:22][C:21]3[C:23]([Cl:31])=[CH:24][C:25]([NH:27][CH2:28][CH2:29]Cl)=[CH:26][C:20]=3[CH2:19][S:18](=[O:33])(=[O:32])[C:17]=2[CH:34]=1)=[O:12]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:35])[C:16]2[O:22][C:21]3[C:23]([Cl:31])=[CH:24][C:25]([NH:27][CH2:28][CH2:29][NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:26][C:20]=3[CH2:19][S:18](=[O:32])(=[O:33])[C:17]=2[CH:34]=1)=[O:12]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3ccccc3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
Benzyl amine (1.08 g, 10.08 mmol) and tetrabutylammonium iodide (0.02 g, 0.054 mmol) were added to a suspension of the carboxylic acid of Example 56k (0.86 g, 2.0677 mmol) in methanol (8 mL) under nitrogen, in a pressure reactor vessel and heated to 110° C. for 4 h. The reaction mixture was concentrated (oily residue), treated with methanolic HCl (25 mL) and refluxed overnight. It was concentrated, treated with an aqueous sodium bicarbonate solution to pH 8 and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 1% methanol/chloroform) to obtain the title compound. Yield: 0.56 g, (54%); 1H NMR (CDCl3): δ 2.62 (s, 3H, CH3), 2.95 (t, 2H CH2), 3.2 (m, 2H, CH2), 3.83 (s, 2H, CH2), 3.9 (s, 2H, CH2), 4.95 (s, 1H, NH), 6.5 (s, 1H, Ar), 6.53 (s, 1H, Ar), 7.4 (m, 5H, Ar), 8.1 (s, 1H, Ar), 8.47 (s, 1H, Ar); MS: m/e (ES+) 501 (M+1).