Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O1CCCC1.[Cu]I>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][C:3]=1[CH3:10]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(I)cc(C)c1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(-n2cncn2)cc(C)c1Br
Temperature: 130 °C

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (500 mg), 1,2,4-triazole (340 mg), potassium carbonate (770 mg), and copper(I) iodide (232 mg) in N-methyl-2-pyrrolidinone is stirred at 130° C. over night. More potassium carbonate (770 mg) and copper(I) iodide (232 mg) are added and the mixture is heated to 150° C. for 4 h. After cooling to room temperature the mixture is diluted with tetrahydrofuran and filtered. The filtrate is concentrated in vacuo and purified by HPLC on reversed phase to give the title compound. LC (method 7): tR=0.99 min; Mass spectrum (ESI+): m/z=252, 254 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]1([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:19]=[C:18]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)[N:17]=2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>O1CCOCC1>[CH:6]1([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[N:19]=[C:18]([C:29]3[CH:30]=[CH:31][C:32]([NH:33][C:37](=[O:38])[O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:35]=3)[N:17]=2)(=[O:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Yield: 90.6 %

Procedure:
Sodium bicarbonate (113 mg, 1.35 mmol) was added to a solution of 4-[4-(cyclohexylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (370 mg, 0.86 mmol) in 1,4-dioxane (5 mL). Phenyl chloroformate (0.124 mL, 0.99 mmol) was added dropwise and the resultant mixture was stirred at RT for 5 hours. The resulting mixture was evaporated to dryness and the residue partitioned between DCM (5 mL) and water (5 mL). The organic layer was separated and evaporated to dryness. The crude residue was triturated with diethyl ether to give the desired material (429 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[CH:16][CH:15]=2)[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:22][CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:25])=[CH:15][CH:16]=1)([CH3:24])[CH3:23]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(-c3ccccc3)n2n1
Temperature: 110 °C
Yield: 49 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent), phenylboronic acid (1.5 equivalents) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.09 equivalents) in 2:1 dioxane/saturated aqueous NaHCO3 (0.125 M with respect to 4G) was warmed to 110° C. in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with methanol, filtered, and purified via preparative HPLC to afford the title compound (49%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6 H), 2.40 (s, 3 H), 3.47 (s, 2 H), 4.76 (br. s., 1 H), 6.40 (s, 1 H), 7.53 (d, J=8.59 Hz, 2 H), 7.58-7.68 (m, 3 H), 7.94-8.04 (m, 3 H), 8.04-8.10 (m, 2 H), 11.19 (s, 1 H). ESI-MS: m/z 401.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.Br[CH2:27][O:28][C:29](=[O:31])[CH3:30].O>CN(C)C=O>[CH3:27][O:28][C:29](=[O:31])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CC(=O)OCBr
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (60 mg, 0.17 mmol, Example 59) and bromomethylacetate (60 mg, 0.39 mmol, Aldrich) in dimethylformamide (1.5 mL) was stirred at room temperature for 6 hours. The solution was poured into water and extracted into methylene chloride (2×). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-acetic acid methyl ester as a white solid. HRMS, observed: 418.1888; Calcd for M+: 418.1885.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[C:45]([Cl:46])=[N:44][CH:43]=[N:42]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([CH:8]1[CH2:13][CH:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[C:45]([Cl:46])=[N:44][CH:43]=[N:42]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCOc2ccccc2-n2ncnc2Cl)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ncnn1-c1ccccc1OCCN1CCC(NCc2ccnc3ccccc23)CC1Cc1ccccc1

Procedure:
100 mg (0.54 mmol) of (2R*,4S*)-2-benzyl-1-[2-(5-chlor-1H-1,2,4-triazol-1-yl)phenoxyethyl]-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 23 mg (0.62 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR52## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.23, FD-MS: M+ =553.
Reaction SMILES: C1(C)C=CC(S(OC[CH:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3C=[CH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)(=O)=O)=CC=1.[C:28]([O-:31])(=O)[CH3:29].[Na+]>C(O)(=O)C>[OH:31][C:28]1[C:29]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:18]=[CH:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[CH:15]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: OC1=Cc2ccccc2C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-p-toluenesulphonyloxymethyldibenzo[a,d]cycloheptene (17 g) in glacial acetic acid (150 ml) was added anhydrous sodium acetate (8.2 g) and the solution refluxed with stirring for 4 h. The solvents were removed in vacuo, the residue dissolved in methanol (100 ml), cooled to 0° C. and enough solid potassium hydroxide added to give pH 14. The suspension was stirred at room temperature for 2 h. then the methanol was removed in vacuo and the residue Partitioned between ether (200 ml) and water (50 ml). The organic layer was washed three times with water (50 ml), then dried and evaporated to qive the crude alcohol which was crystallised from n-hexane/5% ethyl acetate (10.2 g), mp 120°-1° C.
Reaction SMILES: CO.[OH-].[Na+].C([O:8][C:9]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])=[O:12])(=O)C.Cl>O1CCOCC1>[OH:8][C:9]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(C)c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
Methanol (2 mL), dioxane (4 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.77 mL) were added to the obtained methyl 2-(2-acetoxy-3-methylbenzamido)-4-phenylbenzoate (0.062 g), followed by stirring at room temperature for 7 hours. The reaction mixture was adjusted to a pH of 1.1 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.044 g of 2-(2-hydroxy-3-methylbenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:17].C(=O)(O)[O-].[Na+]>O>[Cl:17][C:4]1[C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2sc3c(c12)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ncnc2sc3c(c12)CCCC3
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g) and POCl3 (10 mL) was heated at 55-65° C. for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (20:1), to give the title compound (0.52 g, 60%). 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 3.10-3.07 (m, 2H), 2.88-2.86 (m, 2H), 1.89-1.92 (m, 4H). LC-MS (ESI) m/z 225.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH:23][C:10](=[O:12])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: O=C(O)Cc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1nccnc1N
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nccnc1NC(=O)Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To a solution of (3,5-dichloro-pyrid-2-yl)-acetic acid (Example 5.1) (5.7 g) and 3-amino-pyrazine-2-carboxylic acid methyl ester (4.65 g) in dichloromethane (120 ml) were added successively triethylamine (8.5 ml) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (“BOP-Cl”) (7.5 g). The reaction mixture was stirred at ambient temperature for 24 hours. The organic phase was washed successively with water, aqueous sodium hydrogen carbonate (1M), and brine. The organic phase was dried over magnesium sulfate and concentrated to give 3-[2-(3,5-dichloro-pyrid-2-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (6.37 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 4.35 (s, 2H), 7.77 (s, 1H), 8.39 (s, 1H), 8.49 (s, 1H), 8.56 (s, 1H), 11.02 (s, 1H) ppm.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[I-].[Mg+2].[I-].C(OCC)C>C(OCCCC)(=O)C>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCCCOC(C)=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 120 °C
Yield: 94.5 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.69 g, 18.14 mmol, 1.05 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in butyl acetate (70 mL) respectively, heated to 120° C. Then a solution of magnesium iodide in diethyl ether (0.3 mmol, 0.3 mL) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.88 g yield: 94.50%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[F:18][C:17]1[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ncccc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc(-c2ncccc2F)c1C(=O)O

Procedure:
Combine 3-(3-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (0.515 g, 0.002 mol) with aqueous sodium hydroxide (2N, 8.0 mL, 0.016 mol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir overnight at ambient temperature. Add water and adjust to approx. pH 2.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid (0.44 g, 97%). MS(ES): (M+1)+ 221.9, 222.9 m/z.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccnc2)cc1-c1nc(-c2ccccn2)no1
Yield: 31.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (65 mg, 0.4 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105° C. Standard work up afforded 21 mg (32%) 3-(2-pyridyl)-5-[2-methoxy-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]3([CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:25]1([C:2]2[CH:7]=[C:6]3[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]4([CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]4)[C:5]3=[CH:4][CH:3]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(Br)cc21
Reactant: C1COCCN1
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: CC(C)(C)OC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure N by stirring tert-butyl 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-carboxylate 1′,1′-dioxide (200 mg, 0.48 mmol), morpholine (62.8 μL, 0.721 mmol), sodium tert-butoxide, Pd2dba3 (44 mg, 0.048 mmol) and XPhos (45.8 mg, 0.096 mmol) in toluene (6 mL) at 100° C. for 2 h. Purification by column chromatography (hexanes:EtOAc, 1:0 to 1:1 as eluant) gave tert-butyl 6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-carboxylate 1′,1′-dioxide. Mass Spectrum (ESI) m/e=423.0 (M+1).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]1[O:23][C:22]2[CH:21]=[CH:20][C:18]([O-:19])=[CH:17][C:16]=2[O:15]1.[Na+]>CS(C)=O.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:19][C:18]2[CH:20]=[CH:21][C:22]3[O:23][CH2:14][O:15][C:16]=3[CH:17]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(F)cccc1F
Reactant: [O-]c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Ethyl 2,6-difluorobenzoate (558 mg, 3.0 mmol) was added to dry sodium 3,4-methylenedioxyphenoxide (3.0 mmol, prepared as described in part A) in DMSO followed by addition of dry DMSO (2 ml). The reaction mixture was warmed to 50° C. forming a solution which turned from brown to green upon further heating. After 90 min., the reaction was cooled to 25° C., diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic extract was washed with water (2×7 ml) and brine (7 ml), dried (MgSO4) and concentrated to give a light yellow oil. The product was purified by flash chromatography on SiO2 (5-20% EtOAc/hexane) yielding 532 mg of ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate as a colorless oil (58% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCN
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.37 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-2-(napthalen-2-yloxy)ethylamine, solid, m.p. 105° C., (yield 0.64 gm, 87.6%).
Reaction SMILES: O=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Br[C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:2]1[C:3]([OH:5])=[O:4]
Reactant: CC(=O)C(=O)O
Reactant: Nc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ncccc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.22 mL 2-oxo-propionic acid, 0.26 g palladium acetate and 3.20 mL triethylamine were added to a solution of 1.00 g 2-bromo-pyridin-3-yl amine and 1.21 g triphenyl-phosphine in 10 mL N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at 100° C. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel with dichloromethane/methanol as eluent. Yield: 260 mg MS(ES+): m/e=163.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[N:8][C:9]=1[O:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[Br:1]/[C:12](/[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[C:9]([O:10][CH3:11])[N:8]=1)=[CH:13]\[C@@H:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1
Reactant: COc1nc(/C=C\[C@H]2CCC(=O)N2)ccc1Cl
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Bromine (80 μL) was added to a solution of (5R)-5-[(Z)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (200 mg) in carbon tetrachloride (2 mL) under ice-cooling, and the mixture was stirred at the same temperature (0° C.) for 15 minutes. The reaction solution was concentrated and the residue was dissolved in chloroform. 1,8-Diazabicyclo[5.4.0]undec-7-ene (238 μL) was added under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless powder (164 mg, 62%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>[Cu]I.O1CCOCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH:9]=1
Reactant: Ic1cccnc1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccnc1
Temperature: 125 °C
Yield: 93.7 %

Procedure:
In a sealed flask, a stirred mixture of CuI (37 mg, ˜0.2 mmol) and potassium carbonate (2.70 g, 19.5 mmol) was degassed for 15 min. N,N,N′,N1-tetramethylethylenediamine (146 μL, ˜1.0 mmol), 3-iodopyridine (2.00 g, 9.8 mmol), 2-pyrrolidinone (˜1 g, 11.7 mmol) and 1,4-dioxane (10 mL) were added, respectively (A. Klapars. J. C. Antilla. X. Huang. S. L. Buchwald J. Am. Chem. Soc. 2001, 123, 7727-7729). The flow of nitrogen was removed, and the reaction mixture was then heated at 125° C. for 18 h. After cooling to room temperature the reaction mixture was filtered, rinsed with ethyl acetate, and concentrated. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 5/95) to afford title compound 349 (1.49 g, 94% yield) as a yellow oily liquid. MS (m/z): 163.1 (M+H)+..
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1.C(O)C.O.C(O)(=O)C>[OH-].[Na+]>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Yield: 69.5 %

Procedure:
Ethyl 7,8-methylenedioxy-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a) quinoline-4-carboxylate (1.38 grams, 4.3 mmol) was suspended in a mixture of 2.0 grams of sodium hydroxide, 40 ml of ethanol and 30 ml of water and the whole mixture was heated to reflux for thirty minutes. Then it was acidified with acetic acid when the solution was still hot, the crystals separated out were collected by filtration, washed with water and air dried and the resulting crude crystals were recrystallized from dimethyl formamide to give 870 mg (69.0 percent) of the title compound, melting point 315° to 320° C. (decomposition). Elementary analysis calculated as C13H9NO5S: C 53.61, H 3.11, N 4.81; Found: C 53.68, H 2.92, N 4.66.