Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>O>[C:1]12([C:11]3[CH:12]=[C:13]([S:19]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:42])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(CS(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
844 mg (2 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoate and 20 ml of dichloromethane were introduced into a round-bottomed flask and 386 mg (1.9 mmol) of meta-chloroperbenzoic acid were added. The reaction medium was stirred at room temperature for two hours and was then poured into water and extracted with dichloromethane. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and ethyl ether (90/10). After evaporation of the solvents, 270 mg (30%) of the expected ester, having a melting point of 121°-2° C., were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([OH:23])=O.[NH2:24][CH2:25][CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([NH:24][CH2:25][CH2:26][OH:27])=[O:23]
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Reactant: NCCO
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)NCCO)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and 2-aminoethanol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a 500 ml flask were added 45.6 grams (0.374 mol) 4-hydroxylbenzaldehyde, 150 ml of acetone and 25.8 grams (0.187 mol) potassium carbonate. Then, 52.1 ml (0.449 mol) of benzoyl chloride (BzCl) was added therein dropwise slowly at a temperature of about 0° C. After the addition, the mixture was warmed up to room temperature and the reaction lasted 2 hours. The residue was extracted 3 times with ethyl acetate (150 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated till dry to obtain 76.08 grams (0.336 mol) 4-benzoyloxybenzaldehyde. Next, 35.7 ml (0.37 mol) of 4-fluoroaniline was added dropwise to a solution of the obtained 4-benzoyloxybenzaldehyde in 300 ml of ethyl acetate. The reaction lasted 1 hours. The reaction mixture was filtered. The obtained solid was recrystallized from anhydrous ethanol to obtain 60.3 grams (0.189 mol) white solid, namely compound II-1. 1H NMR (400 MHz, CDCl3): δ 7.09-7.14 (m, 2H, Cpr-H), 7.23-7.28 (m, 2H, Cpr-H), 7.37-7.39 (m, 2H, Cpr-H), 7.54-7.59 (m, 2H, Cpr-H), 7.67-7.71 (m, 1H, Cpr-H), 7.99-8.02 (m, 2H, Cpr-H), 8.24-8.26 (m, 2H, Cpr-H), 8.49 (s, 1H, —CH—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH2:27])[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH:27][C:30](=[O:32])[CH3:31])[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:25])([F:26])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(N2CCC(C(Cn3nc(C(F)(F)F)c(Cl)c3C)NC(C)=O)CC2)ccc1Cl
Yield: 91.1 %

Procedure:
A solution of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (49 mg, 0.109 mmol) in anhydrous DCM (1.5 mL) was treated with acetic anhydride (0.012 mL, 0.130 mmol) and DMAP (1.3 mg, 11 μmol), and the resultant mixture was stirred at RT for 1.5 h. After this time, the mixture was diluted with DCM (5 mL) and then washed sequentially with saturated NaHCO3 and brine. The organic extract was dried (MgSO4) and concentrated in vacuo to give N-(1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl)acetamide (49 mg), which was used without further purification in the reaction below. LC-MS: 493.25, [M+H]+; tR=3.08 min (method b).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[C:17]([CH2:22]Br)=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15]1)([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Temperature: 5 °C
Yield: 73.5 %

Procedure:
Dissolve diethyl malonate (7.6 mL, 50 mmol) in anhydrous tetrahydrofuran (500 mL) and place under an argon atmosphere. Cool to 5° C., add sodium hydride (1.2 g, 50 mmol) and stir briefly until homogeneous. Add α,α'-dibromo-o-xylene (13.2 g, 50 mmol) and stir an additional 15 minutes. Add additional sodium hydride (1.2 g, 50 mmol) and stir for 16 hours while warming to room temperature. Filter, evaporate the solvent in vacuo and purify by silica gel chromatography (1:1 methylene chloride/hexane) to give 2,2-dicarboethoxyindan (9.64 g, 74%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[K+]>CO.CCOC(C)=O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1C(=O)O
Reaction time: 12 h

Procedure:
To a solution of 2 (2.5 g, 11 mmol) in aqueous methanol (30 mL) was added KOH (1 eq, 630 mg). Reaction was heated to 50° C. for 12 hours before the addition of more KOH (630 mg). After 12 hours, the mixture was cooled, diluted with EtOAc and washed with 1M HCl. Aqueous layer was extracted with EtOAc (3×). Combined organic layers, dried over Na2SO4, and concentrated. Product was isolated as an off white solid and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1)[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)COc1cccc(Cl)c1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1cccc(Cl)c1)NCCO[N+](=O)[O-]
Yield: 28.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.79 g of 3-chlorophenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.28 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:50]([O:52][C:53](=[O:64])[CH:54](Br)[CH2:55][CH:56]([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH3:51]>CC#N>[CH2:50]([O:52][C:53](=[O:64])[CH:54]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:55][CH:56]([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH3:51]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(C)CC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)CC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (330 mg, 1.013 mmol) in CH3CN (18 mL) was added Cs2CO3 (825 mg, 2.53 mmol) followed by a solution of 2-bromo-4-methylpentanedioic acid diethyl ester (640 mg, 2.276 mmol) in CH3CN (2 mL) and stirring at reflux temperature was continued for 1.5 h. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentanedioic acid diethyl ester as a pale yellow gum (391 mg, 73%). LCMS: RT 3.59 min [M+H]+ 526.5
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:27])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reaction time: 48 h
Yield: 44.8 %

Procedure:
A solution of 4-bromo-2-methoxyaniline (8.096 g, 40.04 mmol) in dichloromethane (100 mL) was treated with triethylamine (6.06 g, 60.06 mmol), then hydrocinnamoyl chloride (7.08 g, 42.04 mmol). The reaction mixture was stirred for 48 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added. The precipitate was filtered, and the filtrate was evaporated to a solid under reduced pressure. The solid was dissolved in ethyl acetate, and washed with 5 N hydrochloric acid solution, 5 N sodium hydroxide solution, water and brine. The crude material (two spots by thin layer chromatography) was triturated with methanol. The un-dissolved solid was filtered to give 6 g (50%) of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 7.92-7.90 (m, 1H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 7.09-7.07 (m, 1H), 3.83 (s, 3H), 2.90-2.86 (m, 2H), 2.72-2.69 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.491 min (97%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 63.8 %

Procedure:
Reaction of 4,5-diphenyl-1H-imidazole (300 mg, 1.36 mmol), NaH (60%, 55 mg, 1.36 mmol), and SEMCl (289 uL, 1.63 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (304 mg, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.88 (t, 2H, J=7.5 Hz), 3.46 (t, 2H, J=9.0 Hz), 5.12 (s, 2H), 7.27-7.38 (m, 3H), 7.40-1.52 (m, 7H), 7.75 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7]O.P(Br)(Br)[Br:12]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][Br:12]
Reactant: Cc1ccc(Br)cc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1ccc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 181.5 %

Procedure:
To a solution of 24.4 g (0.1214 mol) of 5-bromo-2-methylbenzylalcohol in 200 ml of dry diethyl ether was added dropwise 16.4 g (0.06067 mol) of phosphorous tribromide over 30 minutes with ice-cooling. After the mixture was stirred for 3 hours with ice-cooling, the reaction mixture was added to ice water (500 ml), and the mixture was separated. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and saturated brine, then dried and concentrated to obtain 29.07 g of 5-bromo-2-methylbenzylbromide as crystals.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[C@@H:23]([CH3:27])[CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(OCc5ccccc5)ccc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reaction time: 72 h
Yield: 19.9 %

Procedure:
(11S)-3-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (770 mg, 2.05 mmol) was dissolved in 200 mL of ethanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 430 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) for 3 days. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol and the combined filtrates were concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 30-50% CMA/CHCl3) gave an off-white solid. Recrystallization from acetonitrile and methanol gave (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (110 mg) as a white powder. mp>250° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.49 (br s, 1H), 7.81 (d, J=8.9 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.80 (dd, J=8.9, 2.5 Hz, 1H), 6.42 (s, 2H), 5.05 (d, J=15.4 Hz, 1H), 5.00 (m, 1H), 4.91 (d, J=15.4 Hz, 1H), 4.10 (m, 2H), 1.52 (d, J=6.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 156.7, 152.3, 147.0, 144.2, 132.2, 125.0, 121.6, 112.4, 110.1, 108.2, 68.8, 65.1, 50.3, 19.2; MS (ESI) m/z 271 (M+H)+. Anal. calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 61.99; H, 5.05; N, 20.62.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]1[O:4][CH2:3]1.C([NH:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1)C1C=CC=CC=1>C(O)C>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[N:31]([CH3:36])[C:30](=[O:37])[CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Cn1c(NCCNCc2ccccc2)cc(=O)n(C)c1=O
Reactant: CCCCOc1ccccc1OCC1CO1
Solvent: CCO
Product: CCCCOc1ccccc1OCC(O)CNCCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 10 h
Yield: 74 %

Procedure:
4.5 g of 2-n-butoxyphenyl glycidyl ether ##STR27## are heated under reflux together with 5.8 g of N-benzyl-N'-[1,3-dimethyl-2,4-dioxopyrimid-6-yl]ethylenediamine ##STR28## (in 150 ml of ethanol) for 2 hours. The resulting solution is then cooled and concentrated in vacuo. A resinous residue remains. This residue is dissolved in 150 ml of dioxane (without further purification) and then hydrogenated with H2 in the presence of Pd/C at 20° C. for 10 hours. The catalyst is then filtered of; the filtrate is concentrated; and the residue is recrystallized once from toluene. N-[3-(o-Butoxyphenoxy)-2-hydroxypropyl]-N'-[1,3-dimethyl-2,4-dioxopyrimid-6-yl]ethylenediamine of the formula ##STR29## is thus obtained.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:4])=[O:3].[OH:18]O>CS(O)(=O)=O>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][OH:18])=[O:16])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)CCCCCCCCCCC(=O)O
Reactant: OO
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)CCCCCCCCCCC(=O)OO
Temperature: 40 °C

Procedure:
A stirred mixture of 3 g of 11-(methylsulfonyl)undecanoic acid and 30 mL of methanesulfonic acid was heated to approximately 40° C. The solid dissolved only partially in the methanesulfonic acid at this temperature. Then 1.29 g of 90% hydrogen peroxide was added dropwise. The temperature of the reaction mixture was reduced to room temperature after twenty minutes of reaction time. For the remainder of the two hour reaction time, the reaction mixture was not heated and became homogeneous. The reaction mixture was then cooled in an ice bath forming a solid which was then filtered from solution. The filtrate was poured onto ice prepared from distilled water. A solid formed which was filtered from solution. The two solids collected were combined and washed several times with cold deionized water until the filtrate was no longer strongly acidic. The solid was dried overnight on a watchglass, weighed 2.91 g and had 4.8% by weight active oxygen (84.1% of theoretical).
Reaction SMILES: [OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:18]1([C:24]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[C:33]([F:36])([F:35])[F:34])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])[CH2:19][CH2:20]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a brown solid (51% yield). m.p. 186-189° C. 1H NMR (300 MHz, CDCl3) δ 8.20, 8.04, 7.75, 7.22, 7.07, 6.98, 4.06-3.98, 3.91-3.71, 3.47-3.23, 2.45, 0.96. 13C NMR (75 MHz, CDCl3) δ 166.3, 164.1, 160.1, 160.0, 130.1, 127.2, 116.9, 116.6, 115.0, 114.7, 112.4, 79.4, 46.4, 44.5, 44.3, 41.9, 41.3, 34.4, 25.7. MS (ES+) m/z 498 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[CH3:10][CH:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: CC1CCN(c2ccc(C#N)cc2)CC1

Procedure:
4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 180° C. for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This resulted in the product with the molecular weight of 200.29 (C13H16N2); MS (ESI): 201 (M+H+).
Reaction SMILES: Br[CH:2]([CH:4]1[O:8][CH2:7][CH2:6][O:5]1)[CH3:3].[OH-].[Na+].[CH3:11][NH2:12]>>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH:2]([NH:12][CH3:11])[CH3:3]
Reactant: CN
Reactant: CC(Br)C1OCCO1
Agent: [Na+]
Agent: [OH-]
Product: CNC(C)C1OCCO1
Temperature: 100 °C

Procedure:
2-(1-Bromoethyl)-1,3-dioxolane (60 grams) and 40% aqueous methylamine (160 ml) were charged into a pressure vessel and heated, with agitation, for a period of about 16 hours at a temperature of about 100° C. under autogeneous pressure. At the end of this period, the reaction mixture was cooled to room temperature and 16 grams of NaOH added. The resulting mixture was then extracted with methylene chloride. The extract was dried, then stripped of methylene chloride by use of a rotary evaporator. The residue was distilled to yield the desired product N-[1-(1,3-dioxolan-2-yl)ethyl]methylamine as a fraction boiling at 60° C.-65° C. at about 12 mm Hg pressure.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:12])C1C=CC=CC=1.Cl>CO.[Pd]>[OH:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2)=[O:12]
Reactant: O=C(CCOCc1ccccc1)Nc1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(CCO)Nc1ccc2[nH]ncc2c1
Yield: 58 %

Procedure:
To a solution of 3-(benzyloxy)-N-(1H-indazol-5-yl)propanamide (500 mg, 1.69 mmol) in methanol (100 ml) were added 1N-hydrochloric acid and 10% Pd—C (70 mg), and catalytic reduction was carried out at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in a mixture of chloroform and methanol, followed by adding thereto hexane. The solid precipitated was collected by filtration and dried under reduced pressure to obtain 3-hydroxy-N-(1H-indazol-5-yl)propanamide (201 mg, 58%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:42]4[CH2:43][CH2:44][C:40]([F:45])([F:39])[CH2:41]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: FC1(F)CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Agent: Cl
Product: O=C(N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1)N1CCC(F)(F)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 83 mg (0.58 mmol) of 3,3-difluoropyrrolidine hydrochloride were reacted according to the General Method 6. Yield: 44 mg (45% of theory)
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27](Cl)=O)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>N1C=CC=CC=1.CO>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:4]4[N:5]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:7](=[O:9])[NH:8][C:3]4=[N:1][N:2]=3)[CH2:25][CH2:26]2)=[CH:20][CH:19]=1
Reactant: NNc1nnc(-c2ccccc2)c(=O)[nH]1
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C2(c3nnc4[nH]c(=O)c(-c5ccccc5)nn34)CC2)cc1
Yield: 70.6 %

Procedure:
To a solution of 3-hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one (40.0 mg, 0.197 mmol) in pyridine (0.5 mL) was added 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (0.062 g, 0.30 mmol) and the resulting mixture was irradiated under microwave at 150° C. for 15 min. The reaction mixture was diluted with methanol and purified by RP-HPLC to afford the desired product (50 mg, 70%). Analytical LCMS: (M+H)+=360.2.