Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([N:17]=[N+:18]=[N-:19])[CH2:14][NH:13]1)=[O:11].[CH:20]1([CH:26]=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([N:17]=[N+:18]=[N-:19])[CH2:14][N:13]1[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:11]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC1CCCCC1
Reaction time: 20 h
Yield: 177.7 %

Procedure:
To a solution of (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid methyl ester trifluoro-acetate salt (9.6 g, 33.08 mmol) in 60 mL dichloromethane were added cyclohexanecarbaldehyde (2.6 g, 23.66 mmol), acetic acid (2.5 mL) and sodium triacetoxyborohydride (14.2 g, 66.16 mmol) and the reaction mixture was stirred at room temp. for 20 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated to give (2S,4S)-4-azido-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (11.2 g, crude) as a light brown liquid. The compound was used in the next step without further purification. MS caled. for C13H23N4O2 [(M+H)+] 267.0, obsd. 267.2.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:14]([CH2:24][O:25][CH3:26])[O:13][C@H:12]1[N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([CH2:51][OH:52])=[N:31][C:32]=2[NH:36][CH2:37][CH:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[CH2:53]([O:52][CH2:51][C:30]1[N:29]=[C:28]2[C:33]([N:34]=[CH:35][N:27]2[C@H:12]2[C@H:11]([O:10][Si:3]([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:4])[CH3:5])[C@H:15]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[C@@H:14]([CH2:24][O:25][CH3:26])[O:13]2)=[C:32]([NH:36][CH2:37][CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:31]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: BrCc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CO)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCc4ccccc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.6 %

Procedure:
Sodium hydride (23 mg of an 80% dispersion in mineral oil, 0.76 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methanol (550 mg, 0.76 mmol) (preparation 15) in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 10 min and then benzyl bromide (0.117 ml, 1 mmol) added. The reaction mixture was stirred for a further 24 hr and then the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (3:1) rising in polarity to (2:1) to give the title compound (65 mg) as a gum. MS: 832 (MNa+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:19])([CH3:18])/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C#C)C=CC=CC=1.C[SiH](C)C1C=CC=CC=1COC1CCCCO1.C#CCCCCCC>CCCCCC.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:18])([CH3:19])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC/C=C/[Si](C)(C)c1ccccc1CO
Agent: C#CCCCCCC
Agent: C[SiH](C)c1ccccc1COC1CCCCO1
Solvent: C#Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(/C=C/c1ccccc1)c1ccccc1CO
Yield: 84 %

Procedure:
The same operation as in the preparation of the compound 1a except that phenylacetylene (0.20 g, 2.0 mmol) was used instead of 0.55 g and 2.2 mmol of dimethyl[2-(2-tetrahydro-2H-pyranoxymethyl)phenylsilane (R2 and R3 in (5): methyl group) and 1-octyne, thereby obtaining (E)-(2-(hydroxymethyl)phenyl) dimethyl(2-phenylethenyl)silane (0.45 g, yield of 84%) as a colorless oil, Rf: 0.20 (hexane-ethyl acetate=10:1). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J=7.4, 1.3 Hz, 1H), 7.51-7.41 (m, 4H), 7.37-7.27 (m, 4H), 6.97 (d, J=19.2 Hz, 1H), 6.67 (d, J=19.2 Hz, 1H), 4.79 (s, 2H), 0.52 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.5, 145.2, 138.0, 136.4, 135.3, 130.0, 128.6, 128.3, 127.9, 127.8, 127.1, 126.5, 65.4, −1.2; Anal. Calcd for C17H20Osi; C, 76.07; H, 7.51. Found: C, 75.73; H, 7.55.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 77.9 %

Procedure:
In the same manner as in Example 18-4 and using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (269 mg, 1.92 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (217 mg, 78%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>O1CCCC1>[OH:26][CH:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(C)=O
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.42 h
Yield: 92 %

Procedure:
Under argon atmosphere, 5.6 mL (2.96 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 1 g (2.96 mmol) of 1-trityl-1H-imidazol-4-carbaldehyde in 10 mL of THF at 3˜6° C. The mixture was stirred at 0˜5° C. for 1 hour and 25 minutes. 5.6 mL (2.96 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise at 0˜3° C. The mixture was stirred at 2˜3° C. for 5 hours and 30 minutes. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, recrystallization with 3 mL of IPE afforded 1.16 g of the desired product (yield 92%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].C(CC(O)=O)C1C=CC=CC=1.[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(O)(=O)C>[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH:28]=[N:1][OH:3])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: O=C(O)CCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=NO)CC(=O)OCc1ccccc1

Procedure:
450 g of Sodium nitrite in 600 ml of water are added dropwise, at 0° over 3 hrs. to a solution of 1000 ml acetoacetic acid benzylester (benzylacetate) in 1000 ml of glacial acetic acid and the mixture stirred for 18 hrs. at room temperature. After the addition of 3000 ml of water the mixture is extracted three times with 1500 ml portions of dichloromethane. The combined extracts are washed twice with 500 ml portions of water. Potassium carbonate is added with thorough stirring until the aqueous phase is neutral. The organic phase is separated, dried with magnesium sulphate and the solvent removed in vacuum. The residue is taken up in 5000 ml of di-isopropyl ether, the insoluble material filtered off and the solution again evaporated to dryness. Trituration with petroleum ether and filtration yields the title product
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH3:18])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(CCO)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
To a solution of 2-(4-methoxy-2-nitrophenyl)ethanol (1 g; 5.07 mmol; 1 eq) in THF (50 mL) is added sodium hydride (406 mg; 10.14 mmol; 2 eq) at 0° C. and the reaction mixture is stirred at 0° C. for 10 min before adding iodomethane (0.63 mL; 10.14 mmol; 2 eq). The reaction mixture is stirred overnight. It is quenched by addition of water. The product is extracted with EtOAc and the organic phase is dried over MgSO4. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography using a mixture of petrol ether and EtOAc (70/30) as eluent. The solvents are evaporated to afford 680 mg (63%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 7.35 (d, J=3.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 6.98 (dd, J=9.0, 3.0 Hz, 1H), 3.76 (s, 3H), 3.54 (t, J=9.0 Hz, 2H), 3.24 (s, 314), 3.01 (t, J=9.0 Hz, 2H), HPLC (max plot) 94%; Rt 4.18 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[O:26])[CH:19]=1>>[F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2cc(F)ncn2)cc1
Product: O=C(Nc1ccc(Oc2cc(F)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ESMS: 392.9 [M+H]+; single peak at tR=8.90 min (System 2); Rf=0.14 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH2:25][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(COCc2cccc(-n3cnc4cc(CN5CCCC5)ccc43)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution of compound 12a (80 mg, 0.15 mmol) and pyrrolidine (0.013 mL) in dichloromethane (10 mL) was stirred for 30 min at RT, then sodium triacetoxyboro-hydride (100 mg) was added to the reaction mixture at 0° C. The mixture was stirred for 12 hours at RT. The reaction mixture was quenched with water and the product was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 3:7 mixture of ethyl acetate and pet-ether as the eluent to afford compound 13a (40 mg, 68%) as a solid. Mp 192-194° C.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:31][CH3:32])[CH2:20][O:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(Cl)(C)(=O)=O.C(N(CC)CC)C.[Br-:45].[Li+]>O1CCCC1.O>[Br:45][CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][CH2:20][CH:19]([O:31][CH3:32])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:24]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CBr)c1)OC
Reaction time: 2 h

Procedure:
To a solution of 4 g of 3-[[3-(hexadecyloxy)-2methoxypropoxy]methyl]benzenemethanol and 3.05 g of mesyl chloride in 40 ml of tetrahydrofuran at 0° C. was added over 20 minutes a solution of 2.69 g of triethylamine in 10 ml of tetrahydrofuran. A 7.71 g portion of lithium bromide was added and the mixture was stirred for 2 hours, diluted with water and filtered. The filtrate was poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried and evaporated, giving 4.5 g of 1-(bromomethyl)-3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzene as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([F:13])[C:6]([CH3:12])=[N:7]2.C([Sn](CCCC)(CCCC)[C:19]([O:21]CC)=[CH2:20])CCC.Cl>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.C1(C)C=CC=CC=1>[F:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]([C:19](=[O:21])[CH3:20])[CH:11]=[CH:10][CH:9]=2
Reactant: Cc1nc2cccc(Br)c2nc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2nc(C)c(F)nc12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
A 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, reflux condenser, nitrogen gas inlet, and a temperature probe was charged with 5-bromo-3-fluoro-2-methylquinoxaline (30 g, 124 mmol), Pd(PPh3)4 (4.31 g, 3.73 mmol), toluene (300 mL), and tributyl(1-ethoxyvinyl)tin (Synthonix, Wake Forest, N.C.; 46.2 mL, 137 mmol), and the resulting mixture was heated under N2 atmosphere at 90° C. for 18 hours. The mixture was cooled to RT, HCl (6.0 N, aq.; 12.45 mL, 74.7 mmol) was added, and the resulting mixture was stirred at RT for 10 min. The mixture was extracted with EtOAc (500 mL). The organic layer was separated and sequentially washed with brine (2×200 mL) and saturated aq. NaHCO3 (100 mL) and then concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% DCM/heptane followed by repurification with silica gel, 0-75% EtOAc/heptane) furnished 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126 g; 16.0 g, 78.4 mmol, 63% yield) as an orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (1H, dd, J=8.3, 1.3 Hz), 8.10 (1H, dd, J=7.3, 1.1 Hz), 7.77 (1H, t, J=7.8 Hz), 2.92 (3H, s), 2.79 (3H, d, J=1.6 Hz). 19F NMR (377 MHz, CDCl3) δ ppm −69.81 (1F, s). m/z (ESI, +ve) 205.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].[CH2:17]([Br:20])[CH2:18]C.[CH3:21]O>>[Br-:20].[CH3:1][CH:2]([N+:14]([CH3:21])([CH3:16])[CH2:15][CH2:17][CH3:18])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CO
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: CCCBr
Product: CCC[N+](C)(C)C(C)/C=C/C1C(C)=CCCC1(C)C
Product: [Br-]

Procedure:
A solution of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (5.0 g) and 1-propylbromide (6.0 g) in absolute methanol (10 cc) was refluxed for 3 hours, and the solvent of the reaction mixture was distilled off under reduced pressure. To the residue were added benzene and ether, and precipitated crystals were gathered by filtration to give colorless crystals (0.8 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylpropylammonium bromide.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].Cl.[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][N:54]1[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH2:16][N:4]([C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[F:1])[CH:18]=1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCCN2)cc1OC
Reactant: O=C(O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCCN2C(=O)c2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)c2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=2[Cl:15])=[O:25])=[C:7]([OH:14])[C:6]=1[S:3]([NH:2][CH3:1])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 48.7 %

Procedure:
A solution of N-methyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (70 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (57 μL, 0.44 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 66 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), gave the desired product (60 mg, 49%, three steps). EI-MS (m/z) 422.3, 424.3, 426.3 (M−).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2OC(=O)[C:12](=[C:16]=[O:17])[CH2:11]2)=[CH:2]1.O.[NH2:19][NH2:20].[C:21]([OH:24])(=O)C>COCCO>[OH:24][CH2:21][CH:11]1[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[N:20][NH:19][C:16](=[O:17])[CH2:12]1
Reactant: O=C=C1CC(c2c[nH]c3ccccc23)OC1=O
Reactant: NN
Reactant: CC(=O)O
Solvent: COCCO
Solvent: O
Product: O=C1CC(CO)C(c2c[nH]c3ccccc23)=NN1

Procedure:
3.3 g (b 0.014 mol) of 4-(3-indolyl)-carbonyl-γ-butyrolactone and 0.85 ml (0.018 mol) of hydrazine hydrate are stirred in 50 ml of ethylene glycol monomethyl ether and 1 ml of acetic acid at 80° C. for 18 hours. After 10 ml of petroleum ether have been added to the reaction mixture, the product crystallises with a good purity.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:13]([Cl:12])(=[O:15])=[O:14])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[F:11]
Reactant: Fc1cc(F)c(Cl)c(F)c1Cl
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1c(F)c(Cl)c(F)c(Cl)c1F
Temperature: 80 °C
Yield: 65.4 %

Procedure:
1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and chlorosulfonic acid (10.0 mL, 150 mmol) were mixed at ambient temperature under a nitrogen atmosphere and the reaction was heated at 80° C. for 24 h. The mixture was then allowed to cool to ambient temperature and was poured onto 12 g of crushed ice. The product was extracted with diethyl ether, dried over MgSO4, and the solvent was evaporated to produce 4.9 g of the title compound, which was used without further purification. MS (EI): 300 (30, M+), 298 (28), 263 (100), 199 (80).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 100.1 %

Procedure:
A solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (260 mg, 0.918 mmol) and excess dimethylamine (4.59 mL, 9.18 mmol) in methanol (2 mL) was stirred at rt for 30 min. The solvent was removed in vacuum to afford crude 2-chloro-7-(4-fluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (268 mg, 0.919 mmol, 100% yield). LC-MS (M+H)+=292.3.