Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]1[CH2:15][CH2:16][CH2:17][CH2:18][C:9]=1[CH:8]=2)(=O)[CH3:2].[NH2:20][NH2:21]>Cl.CC(N(C)C)=O.O>[CH3:2][C:1]1[NH:20][N:21]=[C:13]2[C:12]3[CH:11]=[C:10]4[CH2:15][CH2:16][CH2:17][CH2:18][C:9]4=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=12
Reactant: NN
Reactant: CC(=O)c1c(O)c2cc3c(cc2[nH]c1=O)CCCC3
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1[nH]nc2c1c(=O)[nH]c1cc3c(cc12)CCCC3
Temperature: 140 °C

Procedure:
A mixture of 3-acetyl-4-hydroxy-6,7,8,9-tetrahydrobenzo[g]quinolin-2(1H)-one (1-5) (2.0 g, 7.8 mmol, 1 equiv), hydrazine (0.40 mL, 0.41 g, 13 mmol, 1.6 equiv), and catalytic concentrated hydrochloric acid solution (2 drops) in DMA (30 mL) was heated at 140° C. under nitrogen for 16 h. The solution was cooled and diluted with water (30 mL). The precipitate was filtered, washed with hexanes (3×100 mL), and dried to yield 3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-6) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.51 (s, 1H), 10.99 (s, 1H), 7.70 (s, 1H) 7.04 (s, 1H), 2.78 (m, 4H), 2.59 (s, 3H), 1.76 (m, 4H). LRMS m/z (M+H) 254.4 found, 254.1 required.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13](Br)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1.[I:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](I)[N:21]=1>O1CCCC1.CN(C)C=O.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>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:22]3[CH:23]=[N:24][CH:25]=[C:20]([I:19])[N:21]=3)=[N:12][C:11]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Ic1cncc(I)n1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (1.0 g, 3.03 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (10 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2,6-diiodopyrazine (704 mg, 2.1 mmol, 0.7 equiv), Pd(PPh3)4 (175 mg, 0.2 mmol, 5 mol %) in tetrahydrofuran (2 mL) and dimethyl formamide (0.1 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 140° C. for 20 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 40:60, v/v] to afford 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 7%). MS (M+H)+=455.1, Rt=1.53 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:23][C@H:24]1[C@@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26](=[O:35])[NH:25]1>C(N(CC)CC)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([N:25]1[C@H:24]([CH3:23])[C@H:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:27][C:26]1=[O:35])=[O:13]
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A flask was charged with 29.5 g (158 mmol) of 3-(2,4-difluoro-phenyl)-propionic acid, 700 mL of THF, and 82.8 mL of triethylamine. The mixture was cooled to 0° C. and 23.4 mL of trimethyl acetyl chloride was added slowly. The mixture was stirred cold for 1 hour. Then 8.06 g (190 mmol) of LiCl and 28.1 g of (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one was added. The mixture was allowed to warm room temperature and stirred overnight. The solids were filtered off, and the solvent was removed under reduced pressure. The residue was taken up in diethyl ether and washed with sat. aq. ammonium chloride, sat. aq. sodium bicarbonate, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (3:1 dichloromethane/hexanes eluent) to give 54 g (99% yield) of the titled compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][O:18]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:17](=[O:16])[O:18][CH2:19][CH2:20][C:21]=12)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2
Yield: 79.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (0.2 g, 0.88 mmol) was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde (1.2 eq, 0.18 g) to give 0.26 g (79%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(S)-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared as described in Abreo, et al. J. Med. Chem. 1996, 39, 817–825) (9.7 g, 52 mmol) was taken up in dichloromethane (50 mL), treated with triethylamine (8.7 mL, 62 mmol), cooled to 0° C., treated dropwise with methanesulfonyl chloride (4.4 mL, 57 mmol), stirred overnight at ambient temperature, treated with sodium bicarbonate solution (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 10:1, 5:1, 2:1 and 3:2 hexane:ethyl acetate to provide 10.7 g (78%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9 H) 2.27 (m, 2 H) 3.05 (s, 3 H) 3.82 (m, 2 H) 4.28 (dd, J=10.85, 2.71 Hz, 1 H) 4.43 (m, 1 H) 4.54 (dd, J=10.85, 4.07 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(CC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a stirring solution of 8-[(4-fluorophenyl)methyl]-1,4-dioxaspiro[4.5]decane (18 g, 72 mmol) in 100 mL of THF was added 1 M hydrogen chloride in water (70 mL) followed by conc hydrogen chloride (50 mL). The reaction was heated to reflux for 5 h and then cooled to room temperature. The reaction was conc in vacuo to 120 mL and then extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with sat sodium bicarbonate, brine, dried over sodium sulfate, and conc in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 10:1 hexanes:ethyl acetate) to yield 9.6 g of a colorless oil. MS (ESI) 207 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:22](=O)(O)[O-].[Na+]>CO>[CH3:22][O:11][C:10](=[O:12])[CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#C[C@H](CC(=O)O)c1ccc(O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC#C[C@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 265 %

Procedure:
To a solution of (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (25 g) obtained in Step 2 in methanol (125 mL) was added concentrated sulfuric acid (1.25 mL), followed by stirring the mixture at 80° C. for 2.5 hours. After cooling down to room temperature, water (100 mL) and sodium bicarbonate (4.14 g) were added to the reaction mixture, followed by concentration of the mixture. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was distilled azeotropically with toluene to give (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (28.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27].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.C(#N)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:20][C:19]=1[CH3:27]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
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: CC#N
Product: Cc1cc(-c2cnccc2N2CCC(C(N)=O)CC2)ccc1F
Yield: 56 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), 4-fluoro-3-methylphenylboronic acid (16 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (15 mg, 56%), LC-MS (ESI 3.5 min) Rt 1.46 min, m/z 314 (100%, [M+H]+); m/z (ESI) C18H21FN3O requires 314.1663 found [M+H]+ 314.1658.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (300 mg, 0.673 mmol) was suspended in DCM (10 ml). TEA (0.14 ml, 1 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (230 mg) as a yellow solid. The protected hydroxamic acid derivative was dissolved in DCM (10 ml) and treated with 4 M HCl in dioxane (1 ml, 4 mmol). After 1 h the solvents were evaporated, the residue was worked up with 1 M NaHCO3, extracted with DCM, which was dried and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 90:10) to give an orange solid (95 mg) as free base.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([O:17][CH2:16][C:15]([Br:14])([F:19])[F:18])=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC(F)(F)Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCC(F)(F)Br)C12CC3CC(CC(C3)C1)C2

Procedure:
In tetrahydrofuran, 1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl 1-adamantanecarboxylate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethane-sulfonate.
Reaction SMILES: [CH2:1]([O:3][NH:4][CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2].[C:30](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:33])[CH2:31][CH3:32].C(O)(=O)CC>>[CH2:1]([O:3][N:4]([CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:30](=[O:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CCC(=O)On1nnc2ccccc2c1=O
Solvent: CCC(=O)O
Product: CCON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)CC
Yield: 61 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl propionate prepared from propionic acid to give 5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (17.0 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CN1CCc2c(C)c3ccccc3n2C1=O
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A solution of 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (0.9 g) in a mixture of acetic acid and water (4:1, 30 ml) was heated at 65° C. for 3.5 hours. After evaporation of the solvent, the residue was neutralized with aqueous sodium bicarbonate solution and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (0.447 g) as a powder. This powder was dissolved in a mixture of methanol (40 ml) and 12N hydrochloric acid (0.3 ml). The solution was evaporated to 4 ml and then diluted with ether. The solution was allowed to stand at room temperature to give 3,4-dihydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one hydrochloride (387 mg).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>>[ClH:25].[F:24][C:20]1([F:23])[CH2:21][CH2:22][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(F)(F)CC3)cc2C1
Agent: Cl
Product: FC1(F)CCN(c2ccc3c(c2)CNC3)CC1

Procedure:
Prepared in analogy to Example A3(e) from 5-(4,4-difluoro-piperidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Light yellow solid. MS (m/e): 239.3 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>O1CCOCC1>[F:19][C:3]1[C:2]([N:1]=[C:21]=[O:22])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Solvent: C1COCCO1
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N=C=O)cc32)no1
Yield: 100.5 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.33 g) and dioxane (23 g) was prepared. To this mixture was dropwise added trichloromethyl chloroformate (1 g). The reaction mixture was heated under refluxing for 3 hours. The components with lower boiling points were distilled off, and the residue was dissolved in toluene (50 ml). The resulting solution was concentrated under a reduced pressure to dryness, so that the aimed compound, i.e. 6-fluoro-5-isocyanato-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.46 g) was obtained. m.p. 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH2:8][N:9]([CH2:11][CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:7]=1.[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:20][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:9]([CH3:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: CN(CCC(O)c1ccccc1)Cc1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(c2ccccc2)Oc2ccc(Cl)cc2C1
Yield: 55.2 %

Procedure:
A mixture of N-(5-chloro-2-fluorophenyl)methyl-N-methyl-3-hydroxy-3-phenylpropylamine (3.1 g), 50% sodium hydride dispension (480 mg) and DMSO (100 ml) was maintained at 50° under nitrogen for 12h. The mixture was poured onto water (500 ml) and extracted with ether (3×300 ml). The combined organic extracts were washed, dried and evaporated. Chromatography of the residue on silica (Woelm Grade 1) using ethyl acetate as eluant gave the title compound (1.6 g). This was converted to the tosylate in ether/IPA, m.p. 219°-221°. (Found C, 62.2; H, 5.6; N, 2.7%. C17H18ClNO. C7H8SO3 requires: C, 62.65; H, 5.7; N, 3.0%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:16][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
123.0 g (0.96 mol) of 4-piperidinecarboxamide and 90.8 g (1.08 mol) of sodium bicarbonate are introduced under an argon atmosphere into 2 1 of dry toluene. 180.6 g, equivalent to 125.6 ml (1.056 mol), of bromomethylbenzene are added, and the mixture is heated under reflux for 5 h.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:17]2[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: O=C1CN2CCC1CC2
Reactant: COC(Cc1cc(Br)ccc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(Cc1cc(Br)ccc1NC1CN2CCC1CC2)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
Compound 67 (160 mg, 0.615 mmol) and quinuclidin-3-one (115.5 mg, 0923 mmol) were stirred in acetic acid (5 mL) under argon in the presence of anhydrous sodium sulfate (874 mg, 6.150 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (391 mg, 1.845 mmol) was then added and the mixture stirred for 24 hours at room temperature. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows incomplete consumption of 67, thus a second portion of quinuclidin-3-one (38.4 mg, 0.307 mmol) is added and the mixture stirred for a further 20 hours. After dilution with a mixture of 8:1 ethyl acetate:hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5 to 5:95) to yield a colorless residue, 68 (137 mg, 60.3%). 1H NMR (DMSO-d6) δ 1.25-1.39 (m, 1H), 1.53-1.80 (2×m, 3H), 1.86-1.94 (m, 1H), 2.64-2.77 (m, 4H), 2.80 (d, 2H, J=5.2 Hz), 3.14-3.24 (m, 1H), 3.27 and 3.29 (2×s, 6H), 3.34-3.40 (m, 1H), 4.54 (t, 1H, J=5.2 Hz), 5.04 (d, 1H, J=5.8 Hz), 6.43 (d, 1H, J=8.3 Hz), 7.13-7.15 (m, 1H), 7.17 (s, 1H); ESI-MS (m/z, %): 369/371 (MH+, 100%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[NH:12][N:11]=[C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH:9]=[CH:8]1>C(#N)C.O>[Cl:3][C:7]1[N:12]=[N:11][C:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCCOC(=O)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)c1ccc(Cl)nn1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a mixture of phosphorus oxychloride (20 ml) and acetonitrile (40 ml) heated at reflux was added a solution of n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (20 g) in acetonitrile (80 ml). The reaction was heated at reflux for 30 minutes, cooled and added to an ice cooled solution of K2C03 (87.8 g) in water (600 ml) with vigorous stirring. The product was filtered off, washed with water and dried at 60° C. to give n-butyl 6-chloropyridazine-3-carboxylate (17.5 g, 80% yield), mpt 110-111° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([OH:30])=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(C)(C)C.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:27][PH:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(NCCCCC(O[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NCCCCC(O[PH](=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
An acetonitrile (29.7 ml) solution of the benzyl 6-benzyloxycarbonylamino-2-((hydroxyphosphinoyl)oxy)hexanoate (2.97 g) obtained in the above step (a) was added with benzyl alcohol (3.53 ml) and a pyridine (11.9 ml)-acetonitrile (11.9 ml) mixed solution of pivaloyl chloride (4.20 ml), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction system, and the organic substances were extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and pyridine was removed by azeotropic distillation using toluene. The residue was roughly purified by silica gel (Kanto Kagaku Co., 60 N, spherical, neutral) chromatography (300 g, hexane:ethyl acetate=3:2) to obtain crude benzyl 6-benzyloxycarbonylamino-2-((benzyloxyphosphinoyl)oxy)hexanoate (245 g, 68%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.