Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]CC(C)(C)CO.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(Cl)Cl>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH2:1])(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: CC(C)(CN)CO
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient tempurature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s, 1H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a yellow foam, MS (ESI−): m/z=456.3 ([M−H]−).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Yield: 62.6 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation 2 and L-valine (5.85 g), N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (8 g) was obtained as crystals according to a similar manner to that of Example 6.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:24]=2[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[CH3:46])=[O:22])[CH2:17][C@@H:16]1[CH2:47][C:48](=[O:57])[NH:49][CH2:50][C:51]([C:54](=[O:56])[NH2:55])([CH3:53])[CH3:52])=O)(C)(C)C>C(Cl)Cl>[F:45][C:41]1[C:40]([CH3:46])=[C:39]([CH:44]=[CH:43][CH:42]=1)[CH2:38][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]2[N:31]([C:23]=1[C:21]([N:18]1[CH2:19][CH2:20][NH:15][C@@H:16]([CH2:47][C:48]([NH:49][CH2:50][C:51]([CH3:53])([CH3:52])[C:54]([NH2:55])=[O:56])=[O:57])[CH2:17]1)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27]2
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
A 4 N solution of hydrogen chloride in dioxane (0.68 ml, 2.71 mmol) was added to a solution of the compound of step 6 (0.185 g, 0.27 mmol) in 2.7 ml of anhydrous DCM and the mixture stirred at room temperature for 2.5 h. After evaporation of the solvents, the obtained solid was triturated with anhydrous diethyl ether/DCM (9:1) and dried in vacuo at 45° C. to give 0.131 g of the title compound in the form of 3-(2-{(S)-4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-piperazin-2-yl}-acetylamino)-2,2-dimethyl-propionamide hydrochloride as a light green powder with the following characteristics:
Reaction SMILES: Cl[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].Cl>CC1C=C(C)C=C(C)N=1.CO>[CH3:17][O:18][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1nnn2C1CCCCC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CO
Product: COc1cccc2c1nnn2C1CCCCC1
Yield: 34 %

Procedure:
A slurry of 1.5 g of 4-chloro-1-cyclohexylbenzotriazole, 15 g of sodium methoxide, 10 g of cuprous iodide in 50 ml of 2,4,6-trimethyl pyridine (collidine) and 10 ml of methanol was heated at the reflux temperature for 26 hours. The reaction was cooled and poured into 150 ml of 10% hydrochloric acid. The product was extracted with ethyl ether and on evaporation of the solvent, 0.5 g of a oil was obtained which solidified on standing. The product has a melting point of 133°-134°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:9][CH:8]=1.O[Li].O>C(Cl)Cl.O1CCOCC1.O>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C:14]2[N:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cn1
Reactant: CS(=O)(=O)Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(NS(C)(=O)=O)cc2)cn1
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Methanesulfonyl chloride (0.026 mL, 0.33 mmol) was added to a mixture of 3-(4-aminophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one (0.11 g, 0.33 mmol) and TEA (0.093 mL, 0.67 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 2 hours and concentrated in vacuo. The residue was redissolved in 1:1 dioxane and H2O (5 mL) and LiOH.H2O (0.050 g, 1.2 mmol) was added. The mixture was stirred at room temperature for 20 minutes, then extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was conducted by flash chromatography on silica gel, eluting with 10% to 80% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, followed by further purification by reverse-phase chromatography, eluting with 10% to 50% CH3CN in H2O with 0.1% TFA. The desired fractions were basified and extracted to afford the title compound as a white solid (0.075 g, 56%). 1H-NMR (300 MHz, DMSO-d6): δ9.91 (s, 1H), 8.43 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.85-7.98 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.54-7.69 (m, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.05-7.22 (m, 3H), 2.97 (s, 3H), 2.39 (s, 3H). MS (APCI) m/z: 407 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][C:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)=[CH:9][CH:8]=2)([OH:3])=[O:2].Cl.[CH3:39][CH2:40]O>>[CH2:39]([O:2][C:1]([CH2:4][C:5]1[N:6]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=2)[C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][C:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)=[CH:9][CH:8]=2)=[O:3])[CH3:40]
Reactant: CCO
Reactant: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(C(F)(F)F)cn4)ccc32)cc1
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
A mixture of 2-carboxymethyl-1-(4-isopropoxyphenyl)-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid (85 mg, 0.16 mmol, see Example 26), EtOH (0.8 mL) and HCl (1 M in EtOH, 0.1 mL) was heated at reflux for 20 min, concentrated, diluted with water, neutralized with NaHCO3 (aq, sat) and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound. Yield 45 mg (52%), mp 202° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[P:48]([O-])([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>ClCCl.C(#N)C.[Ag]=O>[CH2:59]([O:58][P:48](=[O:49])([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[O:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=[Ag]
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 2-{2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenoxy}-ethanol (240 mg, 0.5 mmol) and triethyl amine (60 mg, 0.6 mmol) in dichloromethane 10 ml and add methanesulfonyl chloride (60 mg, 0.5 mmol). Stir the solution at room temperature for 1 hour and evaporate to dryness. Re-dissolve the residue in acetonitrile, add dibenzyl phosphate (278 mg, 1.0 mmol) and silver oxide (231 mg, 1.0 mmol) and heat at 70° C. for 24 hours. Filter the mixture through a plug of Celite and evaporate the filtrate to dryness. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Br:1]Br.[C:3]1([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1

Procedure:
Step AAA (1): Followed the procedure of B. Miller and H.-S. Wong Tetrahedron 1972, 28, 2369. A solution of bromine (0.348 mL, 6.75 mmol) in CCl4 (5 mL) was added dropwise to a solution of 2-phenylcyclohexanone (1.12 g, 6.43 mmol) in CCl4 (11 mL) at 0° C. The nearly colorless solution was evaporated in vacuo to afford 2-bromo-6-phenylcyclohexanone. The crude product, which is prone to decomposition, was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1>CO.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3[nH]ncc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Reaction time: 12 h
Yield: 99 %

Procedure:
A solution of tert-butyl 4-(1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg; 0.67 mmol; 1.0 eq.) in MeOH (6 mL) was hydrogenated (10 bars) in a Paar instrument in presence of Pd/C (10% Pd moistened 50% H2O; 7.11 mg; 0.07 mmol; 0.10 eq.) at RT. After 12 h, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness to give the title compound as a grey foam (200 mg; 99%). 1H NMR (300 MHz, DMSO-d6) δ 12.94 (brs, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.49-7.43 (m, 1H), 7.28-7.22 (m, 1H), 4.18-4.02 (m, 2H), 2.99-2.67 (m, 3H), 1.83-1.73 (m, 2H), 1.65-1.46 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(4-chloro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester I-2a (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2×18 mL). The combined organic extracts were washed with H2O (2×10 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography using 40% EtOAc in hexane as an eluting solvent to afford the title compound I-4a (93 mg) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>CC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:1][CH2:2][CH2:3][OH:4])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred and cooled mixture of 25 parts of 2-aminoethanol and 135 parts of methylbenzene is added dropwise a solution of 29 parts of 4-fluoro-2-nitrobenzoyl chloride in methylbenzene. Upon completion, stirring is continued for 30 minutes at room temperature. The precipitated product is filtered off, taken up in water and extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated, yielding 28 parts (64%) of 4-fluoro-N-(2-hydroxyethyl)-2-nitrobenzamide as a residue.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 6-morpholinylhexylphthalimide (253 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH:1](=[C:3]1/[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][N:14]3[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:10][C:9]/1=2)\[CH3:2]>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:8]=2[CH2:7][CH2:6][CH2:5][C:4]1=[O:24])[N:14]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[N:13]=[CH:12]3)[CH3:2]
Reactant: C/C=C1/C(=O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1C(=O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of (E)-5-ethylidene-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (3.27 g, 10.21 mmol) in toluene (75 mL) containing 20% Pd(OH)2 on carbon (0.300 g, 0.427 mmol) was evacuated and placed under hydrogen. The reaction was shaken under about 50 psi of hydrogen for about 1 h, then the catalyst was removed by filtration through Celite® and the filtrate concentrated under reduced pressure to yield 5-ethyl-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (7, R1=4-Fluorophenyl, R2=Ethyl) (3.25 g, 99%); LC/MS, method 3, Rt=2.69 min, MS m/z 323 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=0.9 Hz, 1H), 7.84-7.77 (m, 2H), 7.65 (s, 1H), 7.62 (s, 1H), 7.47-7.38 (m, 2H), 4.08 (t, J=7.0 Hz, 1H), 3.33-3.24 (m, 1H), 3.03-2.97 (m, 1H), 2.79-2.72 (m, 1H), 2.43-2.35 (m, 1H), 2.33-2.05 (m, 2H), 1.83-1.59 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:47][C:48]1[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:58][NH2:59].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[Cl:47][C:48]1[C:53]([C:54]([F:56])([F:57])[F:55])=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:58][NH:59][C:14](=[O:16])[C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
5-oxo-1-(phenylmethyl)proline (0.100 g, 0.46 mmol, prepared as described below) was dissolved in a mixture of dichloromethane (2.5 ml) and dimethylformamide (0.5 ml) and to this were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.105 g, 0.55 mmol), 1-hydroxybenzotriazole (0.074 g, 0.55 mmol), and N-ethyl morpholine (0.143 ml, 1.37 mmol). The mixture was stirred for 10 minutes and then {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.115 g, 0.55 mmol) was added and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate (10 ml) was added and the mixture stirred vigorously for 15 minutes. The organic phase was separated with a phase separator and the aqueous phase was washed with further aliquots of dichloromethane (3×10 ml). The organic fractions were combined and dried over magnesium sulphate. The solvent was then evaporated and the residue was purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(phenylmethyl)-D-prolinamide
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]>[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: COC(=O)c1cccnc1-c1cccc(N)c1

Procedure:
n.m.r. (DMSO-d6) δ values include 3.65 (s, 3 H), 5.19 (s, 2 H), 6.58 (dt, 2 H), 6.76 (s, 1 H), 7.05 (t, 1 H), 7.44 (dd, 1 H), 8.02 (d, 1 H), 8.73 (d, 1 H); from 2-(3-nitrophenyl)-3-pyridinecarboxylic acid methyl ester (293 mg) and 10% Pd/C (30 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([O:8][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CC1(C)CC(O)CC(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(OS(C)(=O)=O)CC(C)(C)O1
Yield: 102.8 %

Procedure:
In a manner similar to the method described in example 32a, 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol (5.5 g, 35 mmol) was reacted with methanesulfonyl chloride (6 g, 52 mmol, Aldrich) and triethylamine in dichloromethane to give methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester as a yellow oil (Yield 8.5 g, 100%). The starting material 2,2,6,6-Tetramethyl-tetrahydro-pyran-4-ol was prepared according to the procedures described by Nemeroff, N. et al in J. Org. Chem. 1978, 43(2), 331-334 with slight modification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][OH:12])=[NH:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A stirred mixture of commercially available 2-amino-4-cyano-pyridine [CAS-No. 42182-27-4] (1.0 g, 8.39 mmol), hydroxylamine hydrochloride (1.17 g, 16.8 mmol) and sodium carbonate (0.89 g, 8.39 mol) in water (8 ml) and ethanol (16 ml) was heated under reflux conditions for 3 h. The reaction mixture was evaporated, water (10 ml) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration to yield the title compound (0.87 g, 68%) as an off-white solid. MS (EI) 152.0 [(M)+]; mp 188° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@H:12]([CH:14]3[CH2:15][CH2:16]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCO
Solvent: CCCCCC
Product: C[C@@H](C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 48.5 %

Procedure:
Racemic 3-amino-7-bromo-5-(1-cyclopropylethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 164 (1.1 g) was resolved by HPLC (column: CHIRALPAD AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=800/200(v/v)) to give the title compound (533 mg) having a shorter retention time.