Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])[CH3:25]>>[CH2:24]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:31])[CH3:25]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCNC(=O)CCC(=O)O
Product: CCNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-ethyl-succinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(ethylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=441; RT=1.13 min; UPLC Method I
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=1>C1(C)C=CC=CC=1.CN(C)C(=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>[CH2:18]([O:17][CH2:16][C:12]1[CH:11]=[CH:10][C:15]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)CCI
Reactant: CCCCCC#CCCOCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCCCCC#CCCOCc1ccc(CCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A flask was charged with Zn-Cu couple (200 mg, 3 mmol) solution of ethyl 3-iodopropanoate (510 mg, 2 mmol) in dry toluene (4 mL) and dry N,N-dimethylacetamide (2mL) was added. The mixture was vigorously stirred for 1 hour at room temperature and then heated at gentle reflux for 4.5 hours. After the mixture was cooled to 60° C, a solution of tetrakis(triphenylphosphine)palladium(0)(30 mg, 0.026 mmol) in toluene (2 mL) was added over 1 minute and stirring was continued for 5 minutes at the same temperature. A solution of (45) (309 mg, 1 mmol) in dry toluene (2 mL) was added and the mixture was refluxed for 12 hours. The reaction mixture was allowed to cool to 25° C. and filtered through a Celite pad. The filter cake was washed with ether (50 mL). The filtrate was successively washed with a solution of i N ammonium chloride (10 mL), a solution of saturated sodium hydrogen carbonate (10 mL) and a solution of saturated sodium chloride (10 mL). The aqueous phases were back extracted with ether (30 mL), the combined organic extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc) afforded (46) (165 mg, 51%) as a colorless oil: Rf 0.44 (95:05 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.19 (m, 4 H), 4.51 (s, 2 H), 4.12 (q, J=7.2 Hz, 2 H), 3.55 (t, J=7.2 Hz, 2 H), 2.94 (t, J=8.1 Hz, 2 H), 2.61 (t, J=8.1 Hz, 2 H), 2.46 (tt, J1 =6.9 Hz, J2 =2.1 Hz, 2 H), 2.13 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.40 (m, 6 H), 1.22 (t, J=7.2 Hz, 3 H), 0.88 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 173.01, 140.87, 138.58, 128.68, 127.75, 81.64, 76.67, 72.99, 69.15, 60.53, 36.02, 31.01, 31.18, 28.81, 22.34, 20.28, 18.85, 14.32, 14.12. ##STR14##
Reaction SMILES: N#N.[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](Cl)=[O:37].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Br:3][C:4]1[N:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:36](=[O:37])[CH2:35][C:34]([CH3:40])([CH3:39])[CH3:33])[CH2:17][CH2:18]3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Agent: Cl
Agent: N#N
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 25 °C

Procedure:
To a rapidly stirred, ambient temperature, N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (dihydrochloride (400.5 mg, 1.1 mmol) and 3,3-dimethylbutanoyl chloride [7065-46-5] (0.2 mL, 1.4 mmol) in ethyl acetate (50 mL) was added Hunig's base [7087-68-5] (0.8 mL, 4.6 mmol) and the reaction allowed to stir over night. Once complete, the reaction was washed with brine, dried (MgSO4), and crystallized from chilled ethyl acetate/heptane to afford 392.5 mg of white crystalline powder, mp. 170-171° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 9H) 2.30 (s, 2H) 3.57 (d, J=7.06 Hz, 4H) 3.63-3.72 (m, 4H) 7.26 (d, J=9.92 Hz, 1H) 7.63 (s, 1H) 7.91 (d, J=9.92 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.57, 30.81, 40.12, 43.50, 45.26, 45.34, 99.17, 110.56, 125.96, 131.44, 136.42, 154.89, 169.49. LRMS (ESI) m/z 380.1/382.1 [(M+H)]+, calc'd for C16H22BrN5O: 380.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5](=[N:12][OH:13])[NH2:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(F)c(Cl)c1
Yield: 33 %

Procedure:
To a solution of 3-chloro-4-fluoro benzonitrile (1.0 g, 6.42 mmol) in ethanol (20 mL), was added hydroxylamine hydrochloride (0.665 g, 9.64 mmol), followed by addition of potassium carbonate (2.66 g, 19.28 mmol). The reaction mass was refluxed for 10-12 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with water, acidified with dilute HCl and filtered to afford 0.400 g the desired product. 1HNMR (DMSO-d6): δ 5.95 (s, 2H), 7.42 (t, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.83 (dd, 1H), 9.80 (s, 1H); MS [M+H]+: 189.12.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[F:30][C:31]1[C:39]([F:40])=[C:38]([F:41])[C:37]([F:42])=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:33]2[C:32]3[C:36](=[C:37]([F:42])[C:38]([F:41])=[C:39]([F:40])[C:31]=3[F:30])[NH:35][CH:34]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a solution of N-benzyloxycarbonyl-4-piperidone (20.2 g, 90.6 mmol) in methylene chloride (600 ml) at 0° C. was added trimethylsilyl trifluoromethanesulfonate (35.1 ml, 181.2 mmol) followed by the slow dropwise addition of a solution of 4,5,6,7-tetrafluoroindole (17.1 g, 90.6 mmol) in methylene chloride (300 ml) over 2.5 h. After 1.5 h, triethylsilane (57.9 ml, 362.4 mmol) was added and the reaction was allowed to warm to RT over 30 min. The reaction mixture was quenched with sat. sodium bicarbonate and the separated organic layer was dried over MgSO4 and concentrated in vacuo. The residue was partitioned between 50% acetonitrile/hexanes (1400 ml) and the separated acetonitrile layer was concentrated in vacuo. The solid residue was recrystallized from absolute EtOH to afford N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (66%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[CH2:10][NH2:11].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:11][CH2:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][CH:2]=3)[F:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCC(F)c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(F)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-fluoroethanamine (0.126 g, 0.606 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.114 g, 0.303 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.0412 g, 0.303 mmol) in DMF (2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0697 g, 0.363 mmol. The reaction was stirred for 16 hours at ambient temperature. It was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system eluting with a linear gradient of 5-50% EtOAc in hexanes to yield 161 mg of the title compound (93.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C>CN(C)C=O>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([OH:27])=[C:19]([OH:18])[CH:20]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 195.7 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (846 mg, 3 mmol) in N,N-dimethylformamide (7.5 mL) is added 3,4-dihydroxy benzylamine hydrobromide (660 mg, 3 mmol) and triethylamine (630 μL, 4.5 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.38 g of 6-Bromo-4-[(3,4-dihydroxy-benzylamino)-methylene]-4H-isoquinoline-1,3-dione hydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1>CO.O1CCCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1NCC1CCOCC1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Br)cnc1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.4 %

Procedure:
A mixture of 5-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridin-2-amine (Step C, 792 mg, 2.51 mmol) and 3% platinum on sulfide carbon (N.E.CHEMCAT, 125 mg) in methanol (9 mL) and tetrahydrofuran (9 mL) was stirred at room temperature for 3 h under hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford the crude title compound (764 mg) as red viscous oil.
Reaction SMILES: [C:1](Cl)(=O)C.CO.[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:17]([OH:19])=[O:18])[NH:8]1>CN(C=O)C>[CH3:1][O:18][C:17]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][NH:8]1)=[O:19]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1Cc2ccccc2CN1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C1Cc2ccccc2CN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
Acetyl chloride (0.88 g) was added to methanol (100 ml) with stirring at 0° C. After 10 minutes, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (J. Am. Chem. Soc., 1962, 48, 4487-4494) (2.0 g) was added; the reaction was allowed to warm to room temperature and stirred overnight. DMF (1 ml) was then added and stirring was then continued for a further 24 h. The solvent was removed in vacuo; dichloromethane was added and the solid thus formed was filtered off and partitioned between dichloromethane (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The organic phase was dried (magnesium sulphate), filtered, and the filtrate evaporated in vacuo to yield the title compound as a pale yellow oil (1.0 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[S:9][CH:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>C(OCC)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([C:21]3([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[CH:8][S:9][C:10]=2[CH:15]=1
Reactant: Clc1ccc2c(Br)csc2c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(O)(c2csc3cc(Cl)ccc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A solution of 0.82 mL (0.98 mMol) n-butyllithium in 5.0 mL diethyl ether was cooled to -78° C. under a nitrogen atmosphere. To this cooled solution was added a solution of 0.22 gm (0.89 mMol) 3-bromo-6-chlorobenzothiophene in 10.0 mL diethyl ether. The reaction mixture was stirred at -78° C. for 1 hour and then to it was added dropwise a solution of 0.12 mL (0.98 mMol) 1-methyl-4-piperidone in 5.0 mL and the reaction was stirred an additional 2 hours at -78° C., then was warmed to -20° C. over 55 minutes. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate, diluted with additional diethyl ether and the phases separated. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica chromatography, eluting with toluene containing 10% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.07 gm (25%) of the title compound as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[SH:13].[C:14]1(=[O:32])[N:18]([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21]Cl)[C:17](=[O:27])[C:16]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:15]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[S:13][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[N:18]1[C:17](=[O:27])[C:16]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:15]2[C:14]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1CCl
Reactant: Sc1nccn1Cc1ccccn1
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CSc1nccn1Cc1ccccn1

Procedure:
1-(2-pyridylmethyl)-2-mercaptoimidazole and 2-phthalimidobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(2-pyridylmethyl)-2-(2-phthalimidobenzylthio)imidazole.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4]1)[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:27]3[N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:30]4=[N:31][CH:32]=[CH:33][CH:34]=[C:29]4[N:28]=3)=[CH:15][CH:14]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3CCOC)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred solution of 4-(1-ethyl-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (57.6 mg) in DMF (4 mL) was added NaH (60% in oil, 5.38 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (38.0 mg).
Reaction SMILES: NN[C:3](N)=[S:4].[C:6]1([NH:12][C:13](=[S:16])[NH:14][NH2:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([NH:12][C:13]2[S:16][C:3]([SH:4])=[N:15][N:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNC(N)=S
Reactant: NNC(=S)Nc1ccccc1
Product: Sc1nnc(Nc2ccccc2)s1
Yield: 80 %

Procedure:
The procedure was as described in Example 2, but instead of thiosemicarbazide there were present 83.5 grams of 4-phenylthiosemicarbazide 83.5 grams of 4-phenylthiosemicarbazide. After the cooling and filtering with suction there were isolated 83.6 grams (=80% yield) of 2-phenylamino-5-mercapto-1,3,4-thiadiazole having a melting point of 208° to 210° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:13]=[C:14]([Br:16])[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
To a solution of 3-benzoxazol-2-yl-5-bromo-phenylamine (0.12 g, 0.42 mmol) in pyridine (2.0 mL) at room temperature was added methanesulfonyl chloride (0.14 g, 1.30 mmol) and catalytic DMAP. The resulting mixture was stirred at room temperature for 17 hours. The solvent was removed under vacuum and the residue was purified by preparative TLC eluting with 4:1/hexanes:ethyl acetate to give N-(3-benzoxazol-2-yl-5-bromo-phenyl)-methanesulfonamide (85.0 mg, 55%) as a yellow solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:34])[CH:20]=[C:21]([C:23]([N:25]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH:27]=[CH2:28])=[O:24])[CH:22]=1.CN>C(O)C>[NH2:3][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:34])[CH:20]=[C:21]([C:23]([N:25]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:26][CH:27]=[CH2:28])=[O:24])[CH:22]=1
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1)C1CCCC1
Agent: CN
Solvent: CCO
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCON)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a solution of ethanol (50 mL) and phthalimide 18 (1.8 g, 3.7 mmol) was added 40% aqueous methylamine (25 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vaczio and then chromatographed on silica gel to provide hydroxylamine 19 (0.5 g; 15% from 16). 1H NMR (300 MHz, CDCl3) δ 6.92 (s, 2H), 6.79 (s, 1H), 5.92 (bs, 1H), 5.40 (s, 2H), 5.17 (m, 2H), 4.04 (t, 2H), 3.88-4.03 (m, 3H), 3.82 (t, 2H), 3.88-4.03 (m, 3H), 3.82 (t, 2H), 2.01-2.12 (m, 2H), 1.4-1.9 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:12])[N:3]=[C:2]([Cl:1])[CH:11]=[C:6]12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Cl)cc2n1CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc(Cl)cc2n1CCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a suspension of 8-chloro-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (1 g, 2.32 mmol) and sodium hydride (0.28 g, 6.95 mmol) in N,N-dimethylformamide (10 mL) was added (bromomethyl)benzene (0.40 mL, 2.78 mmol) at room temperature, and stirred for 30 min at r.t. Purification via reverse phase column (0.3% TFA in water/acetonitrile) afforded the title compound (300 mg).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].C[Si](C)(C)[O:14][C:15]1[CH:16]=[C:17]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:18]=[CH:19][C:20]=1[C:21]([O:23][Si](C)(C)C)=[CH2:22]>CO>[OH:6][CH2:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:16][C:15]=1[OH:14])=[O:22]
Reactant: C=C(O[Si](C)(C)C)c1ccc(N2CCOCC2)cc1O[Si](C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: O=C(CO)c1ccc(N2CCOCC2)cc1O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
3-Chloroperoxybenzoic acid (1.48 g, 6.0 mmol) was slurried in hexanes (40 mL) and cooled to −78° C. A solution of 4-(3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-phenyl]-morpholine (1.10 g, 3.01 mmol) dissolved in hexanes (5 mL) was added slowly. The resulting suspension was maintained at −78° C. for 60 minutes then slowly warmed to 22° C. After stirring at 22° C. for 16 hours, the reaction mixture was diluted with methanol and concentrated in vacuo. The residue was redissolved in methanol and concentrated two additional times. The solids were resuspended in EtOAc and washed 2 times with saturated NaHCO3, and once with saturated NaCl then dried over Na2SO4. After concentration, the residue was chromatographed on SiO2 using 2:1 hexane/EtOAc then 1:1 hexane/EtOAc. After concentration, the alcohol was recrystallized from EtOAc. (19% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:19][C@@H:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Yield: 4.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (2.54 g, 0.156 mol) was dissolved in ethanol (100 mL) and N,N-Diisopropylethylamine (4.07 mL, 0.23 mol) was added followed by (S)-1-Aminoindan (2.00 mL, 0.156 mol). The solution was heated to reflux for 2 hours, TLC indicated complete conversion. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 50% ethyl acetate in hexane to afford the title compound (1.95 g, 46%). LC/MS: Rt=1.90 min, ES+ 260 (AA standard).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C#CCOCCn1c(COCC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.83 h
Yield: 78.5 %

Procedure:
Using the general method of Example 12 Part A, 2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (1.5 g, 4.13 mmol) was reacted with iodobenzene (0.51 mL, 4.54 mmol) at 40° C. After 50 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil was partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown oil. The oil was purified by chromatography over silica gel (98/2 dichloromethane/methanol) to provide 1.25 g of 2-(ethoxymethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a brown glassy solid.