Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:11]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc[nH]1
Product: CCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OCC)c1
Yield: 33.1 %

Procedure:
Starting with 10.0 g of ethyl pyrrole carboxylate (72 mmol) and 33 ml (144 mmol) of dodecanoylchloride and following a procedure analogous to the one described above, 7.65 g (33% yield) of the desired product is obtained. 1H NMR (δ ppm, CDCl3): 9.66 (s, br, 1H, NH); 7.51 (dd, J=1.61, 3.40; 1H, α-pyrrolic); 7.26 (dd, J=1.61, 2.60; 1H ; β-pyrrolic); 4.33 (q, 2H, J=7.16 Hz, CO2Et); 2.73 (t, 2H, J=7.53; α-CO CH2); 1.68 (m, 2H, β-CO CH2); 1.35 (t, 3H, J=7.16; CO2Et); 1.23 (m, 16H, alkyl-CH2); 0.85 (t, 3H, J=7.02, end CH3). 13C NMR (δ ppm, CDCl3): 196.21; 160.96; 127.19; 125.88; 124.09; 114.68; 60.92; 39.81; 31.89; 29.60; 29.58; 29.49; 29.45; 29.41; 29.31; 24.62; 22.66; 14.34; 14.08. Exact mass calculated for C19H32NO3 (M+H)=322.238219, found=322.238983.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(O)(=O)C(C1C=CC=CC=1)O.[CH3:36][C@H:37]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1.C([O-])(=O)C([O-])=O.C(O)(=O)C(O)=O>CN(C)C=O>[CH3:36][C@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:38]1
Reactant: C[C@H]1CCCNC1
Reactant: [O-][n+]1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C(O)C(O)c1ccccc1
Agent: O=C([O-])C(=O)[O-]
Solvent: CN(C)C=O
Product: C[C@H]1CCCN(CCCOc2ccc(-c3cc[n+]([O-])cc3)cc2)C1
Yield: 1 %

Procedure:
Following the procedure described in example 47§C, but starting from potassium carbonate (1.71 g), 4-[4-(3-chloropropoxy)phenyl]pyridine 1-oxide (1.09 g), (3S)-3-methylpiperidine mandelate (1.25 g) and N,N-dimethylformamide (20 mL), affords 19 mg of the crude base which is converted to the oxalate with oxalic acid to give 13 mg of (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]-phenyl}pyridine 1-oxide, oxalate.
Reaction SMILES: [CH:1]1([C@H:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[N:13][CH:12]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(C(O)=[O:25])=CN=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C@H:7]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:25])=[N:13][CH:12]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)N[C@H](C)C2CCCCC2)cn1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)c1ccc(CO)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of (R)-N-(1-cyclohexylethyl)-6-methylnicotinamide (2.28 g, 9.3 mmol prepared from the starting 6-methylnicotinic acid) in CHCl3 was added MCPBA (2.24 g, 1.4 eq) and stirred for 2 h at rt. Saturated aqueous NaHCO3 was added and the organics extracted with CH2Cl2, dried over Na2SO4 and concentrated under reduced vacuum. The residue was dissolved in a minimal amount of acetic anhydride and heated to 125° C. for 40 min. The crude mixture was cooled to rt and aqueous NaHCO3 added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was stirred in MeOH (15 mL) and K2CO3 (1 g) for 2 h, concentrated under reduced pressure and partitioned between EtOAc and H2O, Solvent removal and purification by column chromatography (silica gel) using 30-100% EtOAc/hexanes afforded 3.2a as a white solid (920 mg, 38%): 1H-NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.13 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1 H), 5.96 (d, J=8.0 Hz, 1H), 4.84 (s, 2H), 4.15-4.08 (m, 1 H), 1.85-1.04 (m, 14 H)); LC-MS (220 nm), >98%, 263.2 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:10]=12>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH2:16][CH2:17][C:10]=12
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)c(F)c2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccnc4c3CCN4S(=O)(=O)c3ccc(C)cc3)c(F)c2)cc1
Reaction time: 8 h

Procedure:
50 mg (0.09 mmol) of N-[3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]-4-methylphenylsulfonamide (from example XLIV) are dissolved in 30 ml of methanol, and 48.2 mg (0.05 mmol) of 10% palladium on activated carbon are added. The mixture is hydrogenated overnight under a hydrogen pressure of 3.5 bar. The palladium is then filtered off with suction through kieselguhr and washed with ethanol, and the filtrate is concentrated.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([CH3:30])[CH:10]=1)=[O:7])=O.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][CH2:1][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([CH3:30])[CH:10]=1)=[O:7]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(C=O)c3)cc2C)n1
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(CNCCN(C)C)c3)cc2C)n1
Reaction time: 16 h

Procedure:
To 3-formyl-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.100 g, 0.23 mmol) in MeOH (6 mL) was added N1,N1-dimethylethane-1,2-diamine (0.13 mL, 1.1 mmol) and AcOH (0.010 mL, 0.23 mmol). The reaction was allowed to stir for 2.5 h, at which point sodium triacetoxyborohydride (0.096 g, 0.46 mmol) was added. After approximately 16 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was extracted four times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid. Purification by reverse-phase HPLC using acetonitrile/water/TFA as eluent gave 3-((2-(dimethylamino)ethylamino)methyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide as a white solid. MS m/z=512 [M+1]+. Calc'd for C29H33N7O2: 511.63.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.CO>[NH2:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH:38]3[CH2:39][CH2:40]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Temperature: 100 °C

Procedure:
To 23C (0.464 mmol, 260 mg) in NMP (2 mL) was added TFA (0.2 mL). The resulting reaction mixture was heated at 100° C. for 24 hrs. The reaction mixture was diluted with MeOH and purified by HPLC Phenomenex Axia Luna 5 micron 30×100 mm) with 20% to 100% MeOH (0.1% TFA) in water (0.1% TFA) to isolate 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (107 mg, 0.243 mmol, 52.3% yield) as white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.500 minutes. [M+H]=441.12. 1H NMR (400 MHz, MeOD) δ ppm 8.21-8.35 (1H, m), 8.01 (1H, s), 7.96 (1H, d, J=1.76 Hz), 7.33-7.51 (1H, m), 6.07 (1H, s), 3.60-3.85 (1H, m), 3.08-3.27 (1H, m), 2.49-2.66 (1H, m), 2.25-2.45 (2H, m), 2.06-2.28 (2H, m), 1.35-1.69 (4H, m), 0.77-0.97 (2H, m), 0.50-0.73 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1C=CC(C=NO)=[CH:5][CH:4]=1.[Cl:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:16]([C:17]([NH:13][Cl:12])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C=NO)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)NCl)cc1

Procedure:
Dissolved in 65 ml of dimethylformamide were 6.5 g (43 mmol) of 4-methoxybenzaldoxime, followed by the gradual addition of 6.3 g (47 mmol) of N-chlorosuccinimide at room temperature. After the resultant mixture was stirred for 3 hours, 300 ml of water were added to the reaction mixture. The mixture thus formed was extracted with ethyl ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby 4-methoxybenzhydroxamic acid chloride was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][S:35]([NH:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[CH:41][C:40]=1[N:54]1[CH2:59][CH2:58][N:57]([CH2:60][C:61]([NH2:63])=[O:62])[CH2:56][CH2:55]1)(=[O:37])=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.CO.C(Cl)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>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:42]=[CH:41][C:40]([N:54]5[CH2:55][CH2:56][N:57]([CH2:60][C:61]([NH2:63])=[O:62])[CH2:58][CH2:59]5)=[C:39]([NH:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH:44]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2ccc(N3CCN(CC(N)=O)CC3)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)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: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 56.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (100 mg, 0.190 mmol) was coupled with 2-(4-(2-(methylsulfonamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)acetamide (Intermediate 65A) 125 mg, 0.285 mmol) using sodium carbonate (60 mg, 0.567 mmol) and Pd(PPh3)4 (11 mg, 0.0095 mmol) in toluene/ethanol/water (2/2/1 mL). This afforded 82 mg (56.9% yield) after preparative TLC (Silicagel-1000 micron) using 5% ammoniated methanol in DCM as eluent. MS: m/z=757.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][OH:11].[C:12]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[OH-].[Na+].Cl>O.C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:21])=[CH:4][C:3]=1[CH2:10][OH:11]
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccc(O)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C(=Cc2ccc(O)c(CO)c2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-3-(hydroxymethyl)benzaldehyde (1.08 g), indan-1-one (0.94 g), ethanol (30 ml) and 5M aqueous sodium hydroxide solution (1.6 ml) was boiled under reflux for 6.5 hours. The mixture was cooled to ambient temperature and allowed to stand at that temperature for 16 hours. The mixture was diluted with water (45 ml) and then with 5M hydrochloric acid (1.6 ml) which was added with cooling. The precipitate formed was collected by filtration, washed with water and dried to give 2-(4-hydroxy-3-(hydroxymethyl)benzylidene)-1-indan-one, m.p. 194-195° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:29])[NH:15][CH2:16][C:17]1[S:18][C:19]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=2[N:21]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[O:29])[NH:15][CH2:16][C:17]2[S:18][C:19]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=3[N:21]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C

Procedure:
A suspension of (5-fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (1 g, 2.3 mmol) in ethanol (11 mL) was treated with aq 2 N NaOH (6.8 mL, 14 mmol) and stirred at room temperature. After stirring for 1 h, the solution was concentrated in vacuo and acidified to pH 1 with aq 2 N HCl. The resulting solution was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered, and concentrated to give {5-fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid. (0.68 g, 73%) as a white crystalline solid. mp 172–174° C.; Rf 0.38 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 13.25 (br s, 1 H), 9.49 (t, J=6 Hz, 1 H), 7.95 (dd, J1=9 Hz, J2=7.2 Hz, 1 H), 7.78–7.69 (m, 1 H), 7.11 (dd, J1=11.0 Hz, J2=2.3 Hz, 1 H), 6.94 (dd, J1=8.4 Hz, J2=2.4 Hz, 1 H), 4.94–4.92 (m, 4 H). ESI-LC/MS m/z calcd for C17H10F4N2O4S: 414.3. Found 413.0 (M−1)−. Anal. calcd for C17H10F4N2O4S: C, 49.28; H, 2.43; N, 6.76. Found C, 49.26; H, 2.47; N, 6.68.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([F:18])([F:17])[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([F:18])([F:17])[C:8]2=[O:19])[CH2:4]1
Reactant: N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(F)cnc32)C1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncc(F)cc2C1(F)F
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
1-(Trans-3-aminocyclobutyl)-3,3,5-trifluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (0.105 g, 0.358 mmol), 2-chlorobenzothiazole (0.0728 g, 0.429 mmol), and N,N-diisopropylethylamine (0.249 mL, 1.430 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.032 g, 0.082 mmol, 22.9% yield) as a white solid. M+1: 391.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.46-2.56 (m, 2 H) 3.37-3.48 (m, 2 H) 4.58 (m, J=3.50 Hz, 1 H) 5.23 (quin, J=8.61 Hz, 1 H) 5.76 (br. s., 1 H) 7.12 (t, J=7.53 Hz, 1 H) 7.32 (t, J=7.73 Hz, 1 H) 7.56-7.66 (m, 3 H) 8.30 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A solution of pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester (0.50 g, 2.50 mmol), 1-bromo-4-trifluoromethyl-benzene (0.62 g, 2.75 mmol), sodium tert-butoxide (0.36 g, 3.47 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (155 mg, 0.25 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (114 mg, 0.13 mmol) in toluene (5 mL) at 25° C. was purged with nitrogen gas and evacuated three times. The solution was sealed and heated to 120° C. for 14 h. The reaction mixture was cooled to 25° C., unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Solvents were evaporated and the residue was purified by flash column chromatography (80/20 hexanes/ethyl acetate) to afford [1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester (500 mg, 58%) as a light oil.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:14][CH2:13][CH:12]([S:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[BrH:31]>>[BrH:31].[NH:10]1[CH2:14][CH2:13][CH:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3ccc(O)cc3)C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Product: Oc1ccc(SC2CCNC2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
(RS)-4-[1-(Toluene-4-sulfonyl)-pyrrolidin-3-ylsulfanyl]-phenol (1.9 g, 5.44 mmol) in phenol (5.1 g, 54.4 mmol) was treated with HBr (25 ml, 48%). After 4 hours stirring at 100° C., the reaction mixture was cooled to room temperature and quenched with H2O and CH2Cl2. The aqueous phase was washed with CH2Cl2 and concentrated to provide (RS)-4-(pyrrolidin-3-ylsulfanyl)-phenol hydrobromide (1.13 g, 75%) as a brown oil, MS: m/e=196.2 (M+H+). Following the general method of example 74, the compounds of example 75 to example 77 were prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH2:27][O:28]C(=O)C)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C2C3C(=CC(OC)=C(OC)C=3)C(CC)=C(COC(=O)CC)N=2)C=CC=1OC.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH2:27][OH:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCc1c(COC(C)=O)nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Agent: CCC(=O)OCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2c1CC
Agent: Cl
Agent: [Na+]
Product: CCc1c(CO)nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 5 °C

Procedure:
A mixture of 394.0 g (0.926 M) of 1-(3,4-dimethoxyphenyl)-3-(acetoxymethyl)-4-ethyl-6,7-dimethoxy-isoquinoline (compound of Example 20) or 407.0 g (0.926 M) of 1-(3,4-dimethoxyphenyl)-3-propionyloxymethyl-4-ethyl-6,7-dimethoxy-isoquinoline (compound of Example 38) and 2.76 liters of 5% aqueous hydrochloric acid is refluxed for one hour. The reaction mixture is cooled, poured into 1.98 liters of an aqueous 10% solution of sodium hydroxide, cooled to 5° C., the crystals formed are filtered, washed with 4×300 ml of water and dried at 80° to 100° C., giving 365 to 375 g of a crude product, m. p. 160° to 163° C. This product is recrystallized from one liter of ethyl acetate. Yield 322.5 g (91.0%), m. p. 164° to 166° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C.CCOCC>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][NH:3][C:11]1([CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:12]1
Reactant: CN(C(=O)OC(C)(C)C)C1(CCc2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC1(CCc2cccnc2)CC1
Reaction time: 4 h

Procedure:
20 ml of 4N hydrochloric acid in dioxane are added to a mixture containing 4.4 g of the product obtained in Step 2 in 20 ml of dioxane. Stirring is carried out for 4 hours at 20° C. and then 20 ml of ether are added. Crystallisation is observed. The crystals are filtered off, washed with ether and dried at 50° C. and 0.5 torr, allowing the expected product to be obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.ClCCl>[CH2:29]([O:28][CH2:27][O:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(CCO)cc1)C(F)(F)F
Reactant: ClCOCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CCOCOCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4′-(2-hydroxyethyl)-2,2,2-trifluoroacetanilide (5.9 g) in tetrahydrofuran (20 ml) and dichloromethane (20 ml) were added N,N-diisopropylethylamine (5.7 ml) and benzyl chloromethyl ether (3.9 ml) under ice-cooling, and the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 4′-[2-(benzyloxymethoxy)ethyl]-2,2,2-trifluoroacetanilide (9.7 g).