Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[C:34](=[O:37])([O-])[O-:35].[K+].[K+].CS(O[CH:45]1[CH2:50][CH2:49][N:48](OC(OC(C)(C)C)=O)[CH2:47][CH2:46]1)(=O)=O>>[CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([O:10][CH:45]3[CH2:50][CH2:49][N:48]([C:34]([O:35][C:11]([CH3:12])([CH3:2])[CH3:5])=[O:37])[CH2:47][CH2:46]3)[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)ON1CCC(OS(C)(=O)=O)CC1
Agent: [K+]
Product: Cc1nn2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Yield: 183.5 %

Procedure:
The title compound has been prepared according to the similar manner described in 85-B (ii) from 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (490 mg, 1.07 mmol) obtained in Example 31-B-(i), potassium carbonate (444 mg, 3.21 mmol) and 1-[(tert-butoxycarbonyl)oxy]piperidin-4-yl methanesulfonate (897 mg, 3.21 mmol) obtained above. The crude product was purified by basic silica gel column chromatography (EtOAc/hexane=20/80→50/50) to give pure title compound (630 mg, 92%) as a pale yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:58])([CH3:57])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][C:39]=3[F:52])[C:33]([CH2:53][CH2:54][CH3:55])=[N:32][C:31]=2[CH3:56])=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[F:52][C:39]1[CH:40]=[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:42]=[CH:43][C:38]=1[CH2:37][N:34]1[C:35](=[O:36])[C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]([CH3:58])([CH3:57])[CH2:21][OH:20])=[CH:25][CH:26]=2)=[C:31]([CH3:56])[N:32]=[C:33]1[CH2:53][CH2:54][CH3:55]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogen carbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 2.3 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.3 g, 68%).
Reaction SMILES: C1[NH:3]C1.C(N(CC)CC)C.[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21](OCC(F)(F)F)=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(OCC)C>[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:3])=[O:18]
Reactant: C1CN1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1ccccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
Ethyleneimine (2.9 g., 0.068 mole), triethylamine (6.8 g., 0.068 mole) and diethyl ether (250 ml.) are cooled to 0° C. and stirred while adding 2,5-di-(2,2,2-trifluoroethoxy)benzoyl chloride (22.8 g., 0.068 mole). The mixture is allowed to warm to room temperature and filtered. The filtrate is treated with 6.6 N isopropanol-hydrochloric acid mixture and filtered and the solvent evaporated in vacuo to give N-(2-chloroethyl)-2,5-di-(2,2,2-trifluoroethoxy-benzamide, m.p. 87°-88.5° C.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)C.C(N(CC)CC)C.Br.[Br:26][C:27]1[CH:28]=[C:29]([CH2:34]Br)[C:30]([NH2:33])=[N:31][CH:32]=1>CN(C=O)C.O>[Br:26][C:27]1[CH:32]=[N:31][C:30]2[NH:33][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)[CH2:34][C:29]=2[CH:28]=1
Reactant: CCOC(=O)CNCCCN1CCN(C)CC1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(CCCN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.7 %

Procedure:
A solution of [3-(4-methyl-piperazin-1-yl)propylamino]acetic acid ethyl ester (1.80 g, 7.41 mmol) and triethylamine (2.3 mL, 16.4 mmol) in DMF (50 mL) was treated with 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (2.57 g, 7.41 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (100 mL) and then extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 90:10) gave the title compound (0.50 g, 16%) as a colorless oil: MS (ESI) m/e 428 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5cc(F)cc(F)c5OC)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 282 (100 mg, 0.244 mmol) in DCM was added triethylamine (49 mg, 0.4887 mmol). Ethane sulfonyl chloride 337 (47 mg, 0.3665 mmol) was added to the reaction and stirred it for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 338. 1H NMR (400 MHz, CDCl3) δ: 9.58 (s, 1H), 8.52 (d, 1H), 8.17 (d, 1H), 7.84 (s, 1H), 7.72 (m, 2H), 7.09 (m, 1H), 6.82 (m, 1H), 4.31 (m, 1H), 3.96 (m, 2H), 3.68 (s, 3H), 3.06 (m, 2H), 3.00 (m, 3H), 2.29 (m, 2H), 2.14 (m, 2H), 1.40 (m, 5H), 1.25 (m, 5H) and MS ES+502.1.
Reaction SMILES: O=P(Cl)(Cl)Cl.O[C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[ClH:17].CN([CH:21]=[O:22])C>>[Cl:17][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=1[CH:21]=[O:22]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: CN(C)C=O
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Temperature: 0 °C

Procedure:
DMF (106 mL) was stirred under N2 while cooling in an ice/salt bath to 0° C. POCl3 (364 mL) was added dropwise at a rate such that the temperature did not rise above 10° C. The mixture was then stirred at 0° C. briefly and 5-hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole (106 g) was added with constant stirring. The mixture was stirred while slowly heating to 90° C. As the temperature approached 90° C. the reaction became exothermic and HCl gas evolved. The temperature rose to reflux. After the exotherm subsided the mixture was heated at gentle reflux for 16 h. The dark amber solution was cooled to RT and then poured onto 3 kg ice with stirring. The mixture was mixed thoroughly with the ice and more ice added to maintain the temperature below 5° C. The resulting slurry was stirred continuously for 4 h with occasional addition of ice to maintain low temperature. The solid was separated from the liquid phase by drawing the aqueous phase through a sintered glass filter tube. The solid was reslurried with water (4×1 L) and then collected by filtration and air dried. The product was recrystallized from hexane which gave the desired compound as white needles (137 g). m.p. 39-41° C. An additional 30 g product was obtained by concentration of the mother liquor.
Reaction SMILES: [CH3:1]C(OC(=O)C1C=CC=CC=1OCCN)C.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@H:18]1[C:26]([OH:28])=[O:27].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.CN1CCOCC1>C(#N)C>[CH3:1][O:27][C:26]([C@@H:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]1[S:42]([C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)=[CH:37][CH:38]=1)(=[O:44])=[O:43])=[O:28]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CC(C)OC(=O)c1ccccc1OCCN
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.545 g (2.55 mmol) of the hydrochloride of the methyl ester of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid and 10 ml of acetonitrile is prepared and 0.9 g (3.32 mmol) of 4′-fluoro[1,1′-biphenyl]-4-sulfonyl chloride and 0.62 ml of N-methylmorpholine are added. The reaction mixture is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and washed with 3 times 75 ml of water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (98/2; v/v) as the eluent to give 0.83 g of the expected compound in the form of a white solid (yield=79%).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:11][CH:10]([CH2:9][CH2:8][CH2:7][CH:5]([CH3:4])[CH3:6])[CH2:12][CH:13]([OH:14])[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)CCCC(C)CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCCC(C)CC(C)O

Procedure:
Eighty ml. of a 3M solution of methylmagnesium bromide in ether is added slowly to 31 g. of dihydrocitronellal in 250 ml. of dry ether. The mixture is heated at reflux for about one hour, cooled to 0° and treated with saturated aqueous ammonium chloride until reaction subsides. The organic layer is separated and the aqueous layer extracted with ether. The organic layer and ether extracts are combined, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gives 4,8-dimethylnonan-2-ol.
Reaction SMILES: [NH2:1]C1C2C(=CC=C(S(O)(=O)=O)C=2)C=CC=1.C1C2C(=CC=CC=2)C=CC=1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36]([OH:39])(=[O:38])=[O:37]>[Fe]>[NH2:1][C:31]1[C:30]2[C:35](=[CH:26][C:27]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:28][CH:29]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Reactant: O=S(=O)(O)c1ccc2ccccc2c1
Agent: [Fe]
Solvent: c1ccc2ccccc2c1
Product: Nc1cccc2cc(S(=O)(=O)O)ccc12

Procedure:
It is known that 1-amino-naphthalene-7-sulphonic acid can be prepared, for example, by sulphonating naphthalene, nitrating the resulting 2-naphthalenesulphonic acid and subsequently reducing this with iron (Beilstein H XIV, 765 and Ullmann, volume 12, 625 (1960)). 1-Amino-naphthalene-6-sulphonic acid is always formed as a by-product in this preparation and must be separated off.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:19](C#N)#[N:20].N1C=CC=CC=1.Cl>CN1CCCC1=O>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(Br)cc2)CO1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C#N)cc2)CO1

Procedure:
A mixture of 31.3 g. trans-2-p-bromophenyl-5-pentyl-1,4-dioxane, 10 g. Cu2 (CN)2, 120 ml. pyridine and 60 ml. N-methylpyrrolidone is heated for 2 hours to 150°. One cools, adds thereto a solution of 120 g. FeCl3.6H2O in 600 ml. 20% hydrochloric acid, heats to 70° for 1.5 hours, while stirring. Works up as usu 1 and obtains trans-2-p-cyanophenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=[CH:14][CH:13]=1.[C:23](#[N:27])[CH2:24][C:25]#[N:26]>C1(C)C=CC=CC=1.OC(C)C(=O)C>[NH2:26][C:25]1[N:4]([C:3]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:2]=2[CH3:1])[C:13]([CH3:14])=[C:12]([CH3:17])[C:24]=1[C:23]#[N:27]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CCC#N
Reactant: COc1ccc(N)c(C)c1
Agent: CC(=O)C(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-n2c(C)c(C)c(C#N)c2N)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-4-methoxyaniline (10 g) in toluene (120 ml), acetoin and p-toluenesulfonic acid hydrate (44 mg) were added. The mixture was refluxed with heating for 2 hours. After the reaction mixture was cooled to room temperature, malononitrile (4.6 ml) was added to the reaction mixture, and it was refluxed with heating for 12 hours. The cooled reaction mixture was concentrated. The residue was diluted with ether, and filtered to give the title compound (5.73 g) having the following physical data
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CC(C)Cn1c2ccccc2c2cc(Br)ccc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Into a solution of 3 (4.2 g, 13.9 mmol) in THF (80 ml) was added BuLi (2.5 M in hexane, 6.95 ml, 17.4 mmol) dropwise at −78° C. The mixture was stirred at this temperature for 3 hours before 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (4.05 g, 21.75 mmol) was added in one portion. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours, quenched with water, and then extracted with ether. The organic extracts were combined, washed with brine and water, and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by column chromatography on silica gel with hexane/methylene chloride 3:1 (v/v) as the eluent to yield 4 (3.95 g, 81%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.60 (s, 1H), 8.15-8.10 (d, 1H), 7.90-7.85 (d, 1H), 7.45-7.35 (m, 3H), 7.25-7.15 (m, 1H), 4.10-4.09 (d, 2H), 2.42-2.30 (m, 1H), 1.39 (s, 12H), 0.97-0.95 (d, 6H).
Reaction SMILES: C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:14]2[N:15]=[CH:16]C=CC=2N=N1.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:45]3[CH:46]=[C:47]4[C@:52]([C:54](=[O:61])[C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=5)([CH2:53][C:44]=3[CH:43]=[N:42]2)[CH2:51][N:50]([S:62]([C:65]2[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=2)[C:68]([OH:70])=O)(=[O:64])=[O:63])[CH2:49][CH2:48]4)=[CH:37][CH:36]=1.CNC.C(N(CC)CC)C>ClCCl>[F:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[C:45]3[CH:46]=[C:47]4[C@:52]([C:54](=[O:61])[C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=5)([CH2:53][C:44]=3[CH:43]=[N:42]2)[CH2:51][N:50]([S:62]([C:65]2[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=2)[C:68]([N:15]([CH3:16])[CH3:14])=[O:70])(=[O:64])=[O:63])[CH2:49][CH2:48]4)=[CH:39][CH:40]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)c1
Agent: CNC
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)c1
Yield: 11.7 %

Procedure:
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU) (42.7 mg, 0.112 mmol) was added to a solution of (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic acid (57 mg, 0.102 mmol), dimethylamine (51.0 μl, 0.102 mmol) and triethylamine (28.4 μl, 0.204 mmol) in dichloromethane (3 mL). The resultant mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane (5 mL) and washed with a saturated solution of sodium hydrogen carbonate (aqueous, 5 mL). The organic phase was passed through a phase separator and solvent removed to give a yellow solid. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide (7 mg) as a white solid. LCMS (Method F, ES-API): RT 2.24 min, m+H=586.1; 1H NMR (400 MHz, CDCl3): δ 8.68 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.90 (1H, dt, J=7.9, 1.2 Hz), 7.84 (1H, td, J=7.7, 1.7 Hz), 7.74-7.71 (2H, m), 7.61 (1H, dt, J=7.7, 1.4 Hz), 7.57-7.39 (4H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.47 (1H, d, J=2.0 Hz), 5.52 (1H, dd, J=12.1, 2.0 Hz), 4.27 (1H, d, J=16.9 Hz), 3.86-3.77 (1H, m), 3.14 (3H, s), 2.94-2.76 (5H, m), 2.70 (1H, d, J=12.1 Hz), 2.50-2.43 (2H, m).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.O=S(Cl)[Cl:24]>C(Cl)Cl>[ClH:24].[Cl:24][CH2:2][C:3]1[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CO)cc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a stirred solution of N-(2-((3-(hydroxymethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide SLA 41088 (113 mg, 391 μmol) in dry CH2Cl2 (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.28 mL, 3.86 mmol). The mixture was stirred for 1.5 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give N-(2-((3-(chloromethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide hydrochloride SLA 41090 as a yellow solid (135 mg, 100% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[C:4]1=O.[NH2:13][C:14]([NH2:16])=[S:15].[OH-].[K+].Cl>C(O)C.O>[SH:15][C:14]1[NH:16][C:8](=[O:10])[C:5]2[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[C:4]=2[N:13]=1
Reactant: COC(=O)C1CCC(OC)C1=O
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC1CCc2c1nc(S)[nH]c2=O
Temperature: 25 °C
Yield: 41.4 %

Procedure:
3.44 g of methyl 3-methoxy-2-oxocyclopentane-1-carboxylate [prepared as described in step (b) above] and 1.52 g of thiourea were dissolved in 20 ml of ethanol. A solution of 1.4 g of potassium hydroxide in 10 ml of water was then added to the resulting solution, and the mixture was heated under reflux for 3 hours, after which it was cooled to room temperature. 4 ml of concentrated aqueous hydrochloric acid were added to the mixture, and the crystals which precipitated were collected by filtration, washed with water and dried, to give 1.64 g of the title compound, melting above 250° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Procedure J′: 648 mg of 4-Pyridin-3-yl-benzoic acid methyl ester (3.04 mmol) is dissolved in 15 ml of MeOH and 10 ml of 1N NaOH is added. The reaction mixture is stirred at 50° C. for 30 min and room temperature for overnight. MeOH is removed in vacuo and the residue is acidified to pH=4.0 by 1N HCl. Crystals are filtered and washed by water and dried to give 578 mg of 4-pyridin-3-yl-benzoic acid (96%). 1H-NMR (DMSO): 13.1 (br, 1H), 8.98 (m, 1H), 8.64 (m, 1H), 8.17 (m, 1H), 8.07 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.0 Hz), 7.57 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:18].C(N(CC)CC)C.C(OC(Cl)=O)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Agent: CCOC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1c(Cl)ccc2c1C1CCCCC1O2
Reaction time: 2 h

Procedure:
To a cold solution of 0.3 g 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 g ethylchloroformate in 10 ml chloroform. Stirring is continued for 2 hours. This is then added to a cold mixture of 3 g 3-aminoguinuclidine dihydrochloride in 20 ml water containing 7.5 g K2CO3. Stirring is continued overnight. The reaction mxiture is then diluted with chloroform, the two layers separated and the chloroform layer washed twice with water, dried over magnesium sulfate and evaporated to dryness to give 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl]carboxamide as an oily product.