Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH2:22]=[CH:23][CH3:24]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].C1(C)C(C)=CC=CC=1>[CH:23]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:24])[CH3:22]
Reactant: C=CC
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Agent: [W]
Agent: P
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)c1cc2c(c(O)c1-c1ccc3c(c1)CCCC3)CCCC2
Temperature: 140 °C
Yield: 42 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (30.0 g), xylene (5 ml) and phosphotungstic acid (1.5 g) was heated to 140° C. To the mixture was added propylene (8.9 g) slowly via a dry-ice condenser. GC analysis of the reaction mixture indicated that 98% conversion of the 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol. Small amounts of isopropylated xylene were observed as well. The mixture was purified by flash column to give 14.5 g of 3-isopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol, mp 110° C.; 3.7 g of 3,3′-diisopropyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol, mp 152–3° C.; and a mixture (15 g) containing 38% of 3-isopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol and 33% of 3,3′-diisopropyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH:14]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[O:15][C:16](=[S:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)[CH3:2].[CH2:28]([OH:30])[CH3:29]>C(OC(=O)C)(=O)C.[Pd]>[CH2:1]([N:3]([CH2:13][CH:14]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[O:15][C:16](=[S:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:28](=[O:30])[CH3:29])[CH:5]=1)[CH3:2]
Reactant: CCO
Reactant: CCN(CC(OC(C)=S)c1nc2ccccc2s1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC(OC(C)=S)c1nc2ccccc2s1)c1cccc(NC(C)=O)c1

Procedure:
4.17 Parts of N-ethyl-N-(benzthiazolyl-2-thioacetoxyethyl)m-nitroaniline are dissolved in 75 parts of absolute ethanol and 25 parts of acetic anhydride and hydrogenated at 45° using 10% Pd/C as catalyst. The catalyst is filtered off and worked up in the usual manner to furnish N-ethyl-N-(benzthiazolyl-2-thio acetoxyethyl) m-acetamido aniline having the formula ##STR22##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[C@H:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:34]([O:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=2)=[O:35])[CH2:10]1
Reactant: NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-2-(2-aminoethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.12 g) in a mixture of water (20 ml) and tetrahydrofuran (40 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (4 ml) under ice-cooling with stirring, keeping the pH between 8.5-9.5 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours. The reaction mixture was evaporated under reduced pressure and then ethyl acetate (50 ml) was added thereto. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.88 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:29])[CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]([CH3:33])=O>>[CH:1]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH:23]5[CH2:28][CH2:27][N:26]([CH:31]([CH3:33])[CH3:30])[CH2:25][CH2:24]5)=[CH:20][CH:21]=4)[CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:29])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1COC2(CCN(c3ccc(OC4CCNCC4)cc3)CC2)CN1C1CCC1
Reactant: CC(C)=O
Product: CC(C)N1CCC(Oc2ccc(N3CCC4(CC3)CN(C3CCC3)C(=O)CO4)cc2)CC1

Procedure:
The entitled compound was obtained as an orange oily substance, according to the same method as in Example 4-15-(a) or according to a method similar to it but using 4-cyclobutyl-9-[4-(piperidin-4-yloxy)phenyl]-1-oxa-4,9-diazaspiro[5,5]undecan-3-one obtained in Example 8-5-(a) and acetone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:5]=2[N:4]=[CH:3]1.[H][H]>CCO.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[N:4]=[CH:3]1
Reactant: [H][H]
Reactant: Cn1cnc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2c(N)cccc21
Yield: 93.4 %

Procedure:
A suspension of 1-methyl-4-nitro-1H-benzimidazole [2.1 g, 12 mmol, prepared as described in Viktor Milata et. al., Org. Prep. Proced. Int. 25 (6), 703-704 (1993)] and 5% Pd/C (0.21 g) in EtOH (40 mL) was vigorously stirred under an atmoshphere of hydrogen at rt overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the tiltle compound (1.65 g).
Reaction SMILES: [F:1][C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7]C(=O)[NH:5]1.[OH-].[K+]>C(O)C>[NH2:5][C@@H:4]([CH2:3][C:2]([F:1])([CH3:11])[CH3:10])[CH2:8][OH:7]
Reactant: CC(C)(F)C[C@H]1COC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(F)C[C@H](N)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the fluoro derivative (21.0 g) from Step 4 in 90% aqueous ethyl alcohol (216 mL) was added potassium hydroxide (21.9 g). The mixture was heated at reflux for 4 hours and cooled to room temperature. The mixture was then concentrated and co-evaporated with toluene (3×300 mL). The residue was dissolved in dichloromethane (500 mL) and stirred for 0.5 hour. The suspension was filtered through celite and the celite was washed with dichloromethane (3×100 mL). The filtrate was concentrated to dryness to yield (2S)-2-amino-4-fluoro-4-methylpentan-1-ol.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.[C:42](Cl)(=[O:46])/[CH:43]=[CH:44]/[CH3:45]>>[CH3:40][O:39][C:27]1[CH:28]=[C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:22]1[N:23]=[CH:24][C:19]2[CH:18]=[CH:17][C:16](=[O:41])[N:15]([C:11]3[CH:10]=[C:9]([NH:8][C:42](=[O:46])/[CH:43]=[CH:44]/[CH3:45])[CH:14]=[CH:13][CH:12]=3)[C:20]=2[N:21]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Reactant: C/C=C/C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/C(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Yield: 13.6 %

Procedure:
This compound (10 mg, 14% yield) as a yellow amorphous solid was prepared according to the procedures described for Example 1, using 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (1b, 78 mg, 0.14 mmol) and (E)-crotonoyl chloride (Sigma Aldrich, 0.013 mL, 0.14 mmol) as the starting materials. m/z (ESI, +ve ion) 526.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.17 (1H, s), 8.76 (1H, s), 8.17 (1H, br. s.), 7.92 (1H, d, J=9.4 Hz), 7.84 (1H, br. s.), 7.61 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.8 Hz), 6.99 (1H, d, J=7.6 Hz), 6.76-6.86 (1H, m), 6.54 (1H, s), 6.46 (1H, d, J=9.4 Hz), 6.14 (1H, d, J=15.1 Hz), 6.05 (1H, d, J=16.0 Hz), 3.79 (3H, s), 3.05 (4H, br. 2.45 (4H, d, J=4.5 Hz), 2.24 (3H, s), 1.85-1.91 (3H, m).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[Cl:26][C:27]1[N:28]=[C:29]([C:34](O)=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:19]([O:18][C:16]([NH:15][C@H:3]1[C@H:2]([NH:1][C:34]([C:29]2[NH:30][C:31]([CH2:32][CH3:33])=[C:27]([Cl:26])[N:28]=2)=[O:35])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](NC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)nc1Cl
Yield: 69 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl trans(±)-4-amino-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example (79c) (98 mg, 0.28 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (48 mg, 0.25 mmol), WSC hydrochloride (150 mg, 0.78 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 88.2 mg of the title compound as a white solid (69%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][CH:31]([CH3:33])[CH3:30])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: CC(C)=O
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (0.3 g, 0.76 mmol) in CH2Cl2 (5 mL) was added acetone (56 μL, 0.76 mmol) and the solution was stirred for 15 minutes at room temperature. This was followed by the addition of NaBH(OAc)3 (0.242 g, 1.14 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (20 mL) and 2 M NaOH and the bi-phasic solution was stirred for 20 minutes. The mixture was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give the title compound as a white solid (0.19 g, 44%). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.51 (d, 2 H), 7.66 (d, 2 H), 7.30 (t, 2 H), 7.14 (t, 2 H), 6.51 (s, 1 H), 5.13-5.20 (m, 2 H), 4.07-4.16 (m, 1 H), 3.93 (s, 2 H), 3.77-3.87 (m, 1 H), 3.04-3.14 (m, 1 H), 2.83-2.93 (m, 1 H), 2.69-2.79 (m, 2 H), 1.72-1.86 (m, 5H); m/z (APCI+) for C25H30N5OF 436.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8].[Cl:15]SCl.N#N>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8]
Reactant: ClSCl
Reactant: CC(C)(Oc1cccc(F)c1)C(=O)O
Agent: N#N
Product: CC(C)(Oc1cccc(F)c1)C(=O)Cl
Temperature: 25 °C

Procedure:
To 2-(3-fluorophenoxy)-2-methylpropanoic acid (1.70 g, 8.58 mmol) was added dichlorosulfane (15 mL) dropwise under N2 and the mixture was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound as yellow oil, which was used for next step without further purification.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:22][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 2.00 g (20 mmol) of cyclohexanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water, and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.30 g (yield: 92%) of 6-cyclohexyloxynicotinic acid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH:14]2[CH2:20][CH:19]3[N:21](C(OC(C)(C)C)=O)[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]12[NH:21][CH:19]([CH2:18][CH2:17]1)[CH2:20][CH:14]([O:13][NH:12][C:10]([C@@H:7]1[CH2:6][CH2:5][C@@H:4]3[CH2:9][N:8]1[C:2](=[O:1])[N:3]3[O:29][S:30]([OH:33])(=[O:32])=[O:31])=[O:11])[CH2:15]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OS(=O)(=O)O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC1CC2CCC(C1)N2)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 48 (0.077 g, 0.17 mmol) in DCM (7 mL) was added trifluoroacetic acid (0.34 mL, 4.42 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)—N-(8-azabicyclo[3.2.1]oct-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 27 (Table 1) (0.003 g, 7%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[CH:28]=[CH:27][S:26][CH:25]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCc1ccsc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3cc(F)ccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.1 g (0.34 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.77 mL (0.45 mmol) of a freshly prepared 0.58 M solution of 3-bromomethylthiophene in ethyl ether. After standard work-up, 0.13 g (100% of yield) 4-(6-fluoro-1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[S:29][CH2:30][C:31](O)=[O:32])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])[CH3:9].[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(N(CC)CC)C>C1C=CC=CC=1.O1CCCC1>[CH3:21][C:18]([C:15]1[CH:14]=[C:13]([S:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[S:29][CH2:30][C:31]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:32])[CH:12]=[C:11]([C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]=1[OH:17])([CH3:19])[CH3:20]
Reactant: CNCCc1ccccn1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Oxalyl chloride (0.13 g, 0.00105 moles) was added to a cold (10° C.) solution of trans-[[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]cyclohexyl]thio]acetic acid (0.39 g, 0.00095 mole) in benzene (50 ml). The cold bath was removed and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to an oil. The oil was dissolved in toluene (50 ml) and then concentrated once again. The process was repeated using tetrahydrofuran (25 ml) in place of toluene. To a solution of the oil in tetrahydrofuran (50 ml) was added 2-(2-methylaminoethyl) pyridine (0.13 g, 0.00095 moles) and triethylamine (1 ml) and the reaction mixture was stirred at room temperature for 44 hours. After removal of the while solid precipitate by filtration, the filtrate was concentrated to give the crude product as an oil. The product was purified by silica gel chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl.COC(C1C=C2C(C(CC3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=CN2C)=CC=1)=O>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:22][C:13]3[CH:14]=[CH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH:25]=1)[CH:7]=[CH:6]2)#[N:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Product: N#Cc1ccc2c(ccn2Cc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
This compound was prepared from 5-cyanoindole and 3-(quinolin-2-ylmethoxy)benzyl chloride (Example 5a) by the method described in Example 16, part ii. The residue was crystallised from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:41])([F:40])[O:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])([F:22])[F:21])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Br[CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[CH2:51]([O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:23][C:24]([F:43])([F:42])[C:25]([F:40])([F:41])[O:26][C:27]([F:38])([F:39])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])([F:22])[F:21])=[CH:12][CH:13]=2)=[N:4][CH:3]=1)[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOCCOCCBr
Reactant: Oc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Product: CCCCOCCOCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hydroxy-2-[4-(3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy)phenyl]pyrimidine (1.22 g, 1.85 mmol, Example 10) and 1-bromo-2-(2-butoxyethoxy)ethane (0.81 g, 3.62 mmol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 30 volume percent ethyl acetate/hexane, to yield 1.13 g of purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[Cl:24]
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Product: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
Following the procedure outlined in Example 4, 5.00 g (17.1 mmol) of (2-chlorophenyl) diphenyl methanol, designated as T-3 on Appendix A, was treated with 2.5 ml thionyl chloride (34 mmol) according to general method B to give 4.39 g (82%) of (2-Chlorophenyl) diphenyl chloromethane, mp: 131° C.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[C:19]2[NH:28][N:29]=[C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:34][CH2:33]3)[C:18]=2[N:17]=1.C(O)C.[OH-].[Na+].P([O-])(O)(O)=O.[K+]>C1COCC1>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]1[C:25]2[CH:24]=[C:23]([C:26]([NH2:27])=[O:4])[CH:22]=[CH:21][C:20]=2[C:19]2[NH:28][N:29]=[C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([S:38]([CH3:41])(=[O:39])=[O:40])[CH2:34][CH2:33]3)[C:18]=2[N:17]=1
Reactant: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C(N)=O)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 992 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile trifluoroacetate, 63 ml of ethanol, 30 ml of THF and 10 ml of 9.3N sodium hydroxide. After 3 h at reflux, the mixture is cooled and poured into 250 ml of a 1M aqueous solution of potassium dihydrogen phosphate. The mixture is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. The crude solid is dissolved in 20 ml of DMF, and then 1 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 323 mg of 1-hydroxybenzotriazole (HOBT), 170 mg of ammonium chloride and 1 ml of N,N-diisopropylethylamine (DIPEA) are added. After 2 h of stirring at RT, the reaction mixture is poured into water, extracted with AcOEt, washed with a 1M aqueous solution of potassium dihydrogen phosphate and then with saturated aqueous NaCl solution. Drying over MgSO4, filtering and concentration under RP are followed by purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM, methanol and 4N methanolic ammonia (90/10/1 by vol.), to give 321 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (lemon yellow solid). MS (E/I): m/z=500 (M+); 1H NMR: 1.68 (m, 2H); 2.11 (m, 2H); 2.88 (s, 3H); 2.90 (m, 2H); 3.56 (m, 2H); 3.80 (m, 1H); 6.09 (d, J=8.0 Hz, 1H); 7.33 (t, J=8.0 Hz, 2H); 7.57 (broad s, 1H); 7.69 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.36 (broad d, J=8.5 Hz, 1H); 8.45 (d, J=8.5 Hz, 1H); 12.85 (s, 1H).