Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH2:40])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To a solution of compound 288 (0.33 g, 0.581 mmol) in DCM (11.6 mL) was added TFA (0.53 mL, 6.98 mmol, 12 eq.). The reaction mixture was stirred at r.t. for 24 h, concentrated and the residue was purified by Biotage SP1 Flash Purification System (eluent a gradient DCM/MeOH/NH4OH, 95/5/0.1 to 9/1/0.2) to afford 289 as a white solid (0.256 g, 0.548 mmol, 94% yield). Characterization of compound 289 is provided in the Table 6.
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6].[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[Cl:18][C:2]([Cl:1])([Cl:17])[CH2:3][O:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:12][CH:13]=2)[CH2:8]1)=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccccc2C1
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Crude 3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,2,2-trichloro-ethyl ester (D6) (46 g, 150 mmol) was added dropwise over 40 minutes to chlorosulphonic acid (70 ml) cooled with an ice bath to maintain the temperature between 5 and 15° C. The mixture was then allowed to warm to room temperature, stirred for 16 hours, then poured onto crushed ice (500 ml) and dichloromethane (500 ml) added. This mixture was washed with water (3×250 ml), and brine (50 ml) then dried (sodium sulphate), filtered and evaporated to an orange oil which slowly crystallised on standing. This was recrystallised from ether-hexane to give the title compound (D7) as a white crystalline solid (64.5 g 83%); δH (CDCl3) ppm 3.03 (2H, app.t), 3.81-3.86 (2H, m), 4.74-4.85 (4H, m), 7.42 (1H, d), 7.82-7.88 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)=[C:10]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[C:11]3=[O:28])=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.09 mmol) obtained in Step 1 of Example 66 and CH2Cl2 (2 mL, 0.05M) were charged. Pyridine (0.01 mL, 1.2 eq) was added and then the mixture was cooled to 0° C. and treated with acetic anhydride (0.01 mL, 1.2 eq). After being stirred for 15 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by being purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (25.9 mg, 59%).
Reaction SMILES: ClC1C=CC=CC=1CCCN1C(=O)C(COS(C)(=O)=O)=CC(C2C=CC3OCCC=3C=2)=N1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]3[CH:43]=[C:44]([C:49]([O:51]C)=[O:50])[C:45](=[O:48])[NH:46][N:47]=3)=[CH:41][C:36]=2[CH2:35][CH2:34]1.CS(O[CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=1)(=O)=O>>[C:49]([C:44]1[C:45](=[O:48])[N:46]([CH2:58][CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)[N:47]=[C:42]([C:40]2[CH:39]=[CH:38][C:37]3[O:33][CH2:34][CH2:35][C:36]=3[CH:41]=2)[CH:43]=1)([OH:51])=[O:50]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccccc2Cl)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccc(Cl)cc2)c1=O
Yield: 71 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate, to thereby yield the title compound as a yellow powder (yield: 71.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.BrC1C=C2C3(CCNC3)CN([C:38](NC3SC(Cl)=CN=3)=[O:39])C2=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:38]=[O:39])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 23, with the exception that the 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 39 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.C(C(CCCC)COC(=O)CC[SH:38])C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:12]2[N:8]3[C:9]4[C:4]([CH:5]=[CH:6][C:7]3=[N:14][N:13]=2)=[CH:3][C:2]([SH:38])=[CH:11][CH:10]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Temperature: 80 °C

Procedure:
To 7-Iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (1.5 g, 4.0 mmol) in 1,4-dioxane (15 mL) was added iPr2NEt (1.4 mL, 8.1 mmol), and the reaction was degassed with N2 for 10 minutes. 3-Mercapto-propionic acid 2-ethylhexyl ester (975 mg, 4.5 mmol) was added, followed by Pd2dba3 (93 mg, 0.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (117 mg, 0.2 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the thiol intermediate as an oil. The oil was dissolved in THF (9 mL) and cooled to −78° C. Sodium tert-butoxide (780 mg, 8.1 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with 1N NaOH, and the aqueous layer was washed with Et2O. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10e.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[OH-].[Na+:26]>O>[OH2:15].[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([O-:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[Na+:26]
Reactant: CC1CCc2c(-n3ccnc3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCc2c(-n3ccnc3)c(F)cc3c(=O)c(C(=O)[O-])cn1c23

Procedure:
To a mixture of 0.500 g (1.53 mmole) of 6,7-dihydro-9-fluoro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (from Example 1) and 10 ml of water was added 15.3 ml of 0.1N aqueous sodium hydroxide (1.53 mmole). The mixture was filtered, an equal volume of ethanol added, and the solution evaporated to dryness to give tan crystals of sodium 6,7-dihydro-9-fluoro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate hydrate, m.p.>250° C. Analysis: Calculated for C17H13FNaN3O3.1.25H2O: %C, 54.9; %H, 4.2; %N, 11.3; Found: %C, 54.9; %H, 4.4; %N, 10.7.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=4[N:13]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:35]1[N:36]([C:40]2[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=2[C:42](O)=[O:43])[N:37]=[CH:38][CH:39]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([N:8]3[C@@H:1]4[C@@H:6]([CH2:5][CH2:4][N:3]([C:42]([C:41]5[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=5[N:36]5[N:37]=[CH:38][CH:39]=[N:35]5)=[O:43])[CH2:2]4)[CH2:7]3)=[N:13][C:12]=2[CH:14]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Clc1ccc2oc(N3C[C@@H]4CCNC[C@@H]43)nc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1ccccc1-n1nccn1)N1CC[C@H]2CN(c3nc4cc(Cl)ccc4o3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 2-((1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl)-5-chlorobenzo[d]oxazole (Intermediate 32) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C22H19ClN6O2, 434.89; m/z found 435.1 [M+H]+. 1H NMR (CD3OD): 8.03-7.28 (m, 6H), 7.23-6.88 (m, 3H), 4.72-4.54 (m, 1H), 4.35-3.96 (m, 3H), 3.90-3.35 (m, 3H), 3.13-1.71 (m, 3H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]1([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH3:6][N:4]([CH:3]=[C:19]1[C:18](=[O:21])[CH:17]=[CH:16][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20]1)[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Solvent: CN(C)C=O
Product: CN(C)C=C1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Temperature: 20 °C
Yield: 56.1 %

Procedure:
4.77 g of N,N-dimethylformamide dimethyl acetal are added to a solution of 2.48 g of 4,4-diphenylcyclohex-2-enone in 20 Cm3 of N,N-dimethylformamide. The mixture is refluxed for about 4 hours. After cooling to a temperature in the region of 20° C., the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of diisopropyl ether and allowed to precipitate for about 20 hours at a temperature in the region of 20° C. The solid is drained by suction, washed with three times 10 cm3 of diisopropyl ether and then dried under reduced pressure (13 kPa) over potassium hydroxide at a temperature in the region of 20° C. 1.7 g of 6-dimethylaminomethylene-4,4-diphenylcyclohex-2-enone are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][CH2:17]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][C:16]3([O:20][CH2:19][CH2:18][CH2:17]3)[CH2:21][CH2:22]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:31]1[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=[C:30]1[CH3:29])=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC3(CCCO3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCCO4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 8-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-1-oxa-8-azaspiro[4.5]decane and 2-methybenzimidazole were reacted to give 370. LCMS m/z: 503.2 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[CH:11][C:2]([Cl:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(Cl)nc3cc(CBr)ccc23)cc1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluorophenyl)-7-methylquinoline (2.0 g, 7.4 mmol), N-bromo-succinimide (1.57 g, 8.8 mmol) and AIBN (30 mg, 0.18 mmol) in CCl4 (40 mL) was refluxed for 16 h. The solution was then cooled to rt, filtered and concentrated. Purification on silica gel (eluting with dichloromethane/hexanes, 1:1) gave the title compound. MS (+ESI): 351 (M+H)+.
Reaction SMILES: FC1C=CC=C(F)C=1C#[N:5].[OH-].[Na+].OO.C([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1C(N)=O)C1C=CC=CC=1.ClCl>C(O)C1C=CC=CC=1.O>[NH2:5][C:24]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:23]=1[OH:22]
Reactant: NC(=O)c1c(F)cccc1OCc1ccccc1
Reactant: N#Cc1c(F)cccc1F
Agent: ClCl
Agent: OO
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: O
Product: Nc1c(O)cccc1F
Yield: 51 %

Procedure:
69.9 g (0.5 mol) of 2,6-difluorobenzonitrile and 237 g (1.2 mol) of 6-normal sodium hydroxide solution are initially introduced in 200 ml of benzyl alcohol. 221 g (1.95 mol) of 30% hydrogen peroxide solution are added dropwise to this mixture within the space of 30 min, the temperature rising from 20° C., at the beginning of the metering-in, to 50° C., and then being maintained at this value. After 5 h (complete transformation to 2-benzyloxy-6-fluorobenzamide can be demonstrated by GC), the mixture is cooled and supplemented with 200 g of water and 60 g (1.5 mol) of sodium hydroxide. Chlorine is passed in (8-10 l/h) at 30° C. for 2 h, with the reaction being monitored by gas chromatography and terminated once the amide has disappeared. The phases are separated, 180 g of methanol are added to the organic phase, and further processing is carried out as indicated in Example 8. 32.4 g (0.255 mol, 51%) of 2-amino-3-fluorophenol are obtained as a brown-black powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[CH2:22][C:21](=[O:23])[NH:20][C:17]2=[N:18][CH:19]=1.C(N(C(C)C)CC)(C)C.N1C2C(=CC=CC=2)CC1=O.FC(C1N=CC=CN=1)(F)F>[Cl-].[Zn+2].[Cl-].C(O)(C)(C)C.ClCCCl.ClCCCl.C(O)(C)(C)C>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:15]=[C:16]3[CH2:22][C:21](=[O:23])[NH:20][C:17]3=[N:18][CH:19]=2)[N:5]=1
Reactant: Nc1cnc2c(c1)CC(=O)N2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: FC(F)(F)c1ncccn1
Agent: O=C1Cc2ccccc2N1
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cnc2N1
Temperature: 25 °C
Yield: 13 %

Procedure:
211 mg (0.972 mmol) 5-trifluoromethyl-2,4-dichloropyrimidine was taken into 1.00 mL 1:1 tert-butanol:1,2-dichloroethane mixture. To this was added 972 mL (0.972 mmol) zinc chloride solution. 145 mg (0.972 mmol) 5-Amino-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one was taken into 500 mL tert-butanol/1,2-dichloroethane mix with 169 mL (0.972 mmol) diisopropylethylamine and 2.92 mL (2.92 mmol) zinc chloride solution. Allowed both solutions stir at ambient temperature for thirty minutes. The oxindole-bearing solution was slowly added drop-wise to the solution containing the trifluoromethylpyrimidine. Allowed the combined solutions to stir at ambient temperature for sixteen hours. The volatiles from the reaction mixture were removed under reduced pressure. The resulting glass was taken up into 10% methanol in dichloromethane and washed thoroughly with 1 N sodium hydroxide. Organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a yellow solid. The titled compound was obtained through purification of this yellow solid over silica (97.8:2:0.2 CHCl3:CH3OH:NH4OH) as a yellow solid in a 13% yield (43 mg, 0.130 mmol). APCI m/z 330.0/331.9 (MH+), 1H NMR (D6-DMSO) δ 10.96 (s, 1 H), 10.57 (s, 1 H), 8.74 (s, 1 H), 8.23 (s, 1 H), 7.85 (s, 1 H), 3.56 (s, 2 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CCCN1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1

Procedure:
Distilled THF (5 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one (104 mg, 0.33 mmol), thionyl chloride (86.83 mg, 0.73 mmol, 0.05 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one was produced as an orange oil (105 mg, 0.33 mmol) which was used immediately without further purification. Distilled THF (6 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (211.2, 0.66 mmol), cis-cyclopentene diol (330 mg, 3.3 mmol) and potassium carbonate (456 mg, 3.3 mmol) as for general procedure B. Removal of the solvent yielded the crude product as a colourless oil (160.2 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as an colourless viscous oil. (129 mg, 0.43 mmol, 51% yield). 1H NMR: (300 Hz, DMSO) δ ppm 0.76 (t, 3H, H11), 1.36 (m, 1H, H13/H13′), 1.49, 1.76 (m, 1H, H13/H3′), 3.12 (m, 2H H10) 3.96 (m, 1H, H9/H9′), 4.26 (m, 1H, H9/H9′), 5.29, 5.87, (dd, 1H, H15/H16) 5.74, 5.79 (dd, 1H, H15/H16) 7.23 (d, 1H), 7.38 (m, 4H, H1-H5), 7.61 (m, 2H, H6-H7), 7.76 (d, 1H, H8). IR: 1365, 1682, 2969, 3363 cm−1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)cc2)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of intermediate (b), N-BOC-(R)-2-(4-hydroxybenzyl)morpholine (1.0 g, 3.41 mmol) in anhydrous N,N-dimethyl formamide (10 mL), under at atmosphere of nitrogen at room temperature was added N-bromosuccinimide (0.63 g, 3.58 mmol). The resulting solution was stirred at room temperature for 2 hrs and then poured into water (50 mL) and extracted with ethyl acetate (70 mL×2). Combined organic layers were washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The material was concentrated onto sodium sulfate and purified by column chromatography (silica; 17% ethyl acetate/isohexane) to yield the desired intermediate (a), N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, as a white solid (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([O-])(=[O:20])=[O:19])=[CH:13]3)=[C:4]([O:22][CH3:23])[CH:3]=1.[Na+].S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([Cl:27])(=[O:20])=[O:19])=[CH:13]3)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)[O-])ccc12
Agent: [Na+]
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Cl)ccc12
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A round bottom flask was charged with sodium 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonate (0.137 g, 0.369 mmol) and a septum was attached and the flask flushed with N2. DMF (1.232 mL) was added followed by thionyl chloride (0.081 mL, 1.108 mmol) by syringe at rt, an exotherm was observed. The solution was maintained at rt for 1 h, and then poured into a separatory funnel containing ice. The resulting mixture was extracted with DCM (2×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4 and concentrated to give 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonyl chloride (0.121 g, 0.329 mmol), which was used immediately without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:27][CH2:28]3)[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (394 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 1-(4-piperidinylmethyl)-4-(4-pyridyl)piperidine hydrochloride (550 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-[1-(4-trifluoromethylphenylsulphonyl)-(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (395 mg): NMR (CDCl3): 1.30 (m, 2H), 1.45 (m, 1H), 1.80 (m, 6H), 2.00 (dt, 2H), 2.20 (d, 2H), 2.30 (dt, 2H), 2.40 (m, 1H), 2.90 (d, 2H), 3.80 (d, 2H), 7.10 (d, 2H), 7.80 (d, 2H), 8.50 (d, 2H); m/z 468 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:15]=[C:16]([OH:21])[C:17](=[CH:19][CH:20]=1)[OH:18])([CH3:13])([CH3:12])[CH3:11]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:18][C:17]2[CH:19]=[CH:20][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:15][C:16]=2[O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Product: CC(C)(C)c1ccc(Oc2ccc(C#N)cc2)c(Oc2ccc(C#N)cc2)c1
Yield: 96.1 %

Procedure:
The compound 4-fluorobenzonitrile was reacted with 4-tert-butylcatechol according to the procedure of Example 1. The product was recrystallized from methanol/water (3:1) to give a 96.1% yield of the title compound with the formula: ##STR13##