Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[ClH:22].[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C.Cl>C(#N)C.C(O)(C)C>[ClH:22].[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH2:23])[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: NC1CCCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Nc1c(F)c(N2CCCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.3 g), 3-aminopiperidine hydrochloride (0.905 g), triethylamine (3.0 g) in acetonitrile (40 ml) was refluxed for 5 hours and the reaction mixture was then cooled to room temperature. Removal of the solvent followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave a yellow crystalline substance [MS m/e: 378 (M+)]. The crystalline substance thus obtainedwas suspended in isopropanol and the suspension was adjusted to pH about 1-2 with 10% aqueous hydrochloric acid. Filtration of the precipitated crystals followed by recrystallization from ethanol afforded hydro-chloride of 5-amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.6 g). m.p. 265° C. (decomposition).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:11]([N:30]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O[C@@H]1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of anhydrous dichloromethane (35.0 mL) in a 3-necked flask with a thermometer, oxalyl chloride (1.5 mL) was added and the resulting solution was cooled to −60° C. A solution of dimethyl sulfoxide (2.6 mL) in dichloromethane (7.5 mL) was added over a period of 10 min, and then (3R)-1-tritylpyrrolidin-3-ol (5.0 g) in dichloromethane (15.0 mL) was added over a period of 10 min. The resulting solution was stirred at −60° C. for 15 min., then triethylamine (10.6 mL) was added over a period of 5 min. A white precipitate was formed. After 5 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. Water (45 mL) was added. The mixture was stirred for an additional 30 min and then extracted with dichloromethane. The organic phase was washed with 5% aqueous citric acid solution, dried over anhydrous sodium sulfate, filtered and concentrated to yield the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([Cl:19])=[O:15]
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.1 %

Procedure:
To a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetic acid (833 mg, 3.03 mmol) in dichloromethane (10 mL) were added oxalyl chloride (0.29 mL, 3.33 mmol) and dimethylformamide (1 drop) under argon atmosphere. The mixture was stirred for 3.5 hours at room temperature, then was concentrated to dryness under reduced pressure. Dichloroethane (15 mL) was added, and resulting solution was back evaporated to dryness to obtain crude (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (917 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CC[N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38].C(NC(C)C)(C)C>O1CCCC1.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C

Procedure:
To a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.10 g) in tetrahydrofuran (5 ml) was added DMF (0.005 ml) and oxalyl chloride (0.175 ml). After 0.5 h DIPEA (0.13 ml), diisopropylamine (0.20 ml) and DMAP (0.002 g) were added. After 18 h the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with brine and dried over magnesium sulphate. Filtration and evaporation gave the crude product which was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (1:3). This afforded the title compound as a colourless gum (0.078 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3cc4ccccc4n3C)CC1)O2
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3, was stirred for 10 minutes, then extracted with DCM and treated with N-methyl-indol-2-carbaldehyde (95 mg, 0.60 mmol) and sodium triacetoxyborohydride (159 mg, 0.750 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (179 mg) as a white solid. The resulting ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (187 mg) as an orange solid (hydrochloride salt). The product was suspended in DCM (3 ml), TEA (0.08 ml, 0.58 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (37 mg) as a light yellow solid. The compound was then dissolved in DCM (3 ml) and treated with 4 M HCl in dioxane (0.1 ml, 0.4 mmol) as described in Example 55, Step D, giving a light yellow solid after aqueous workup and column chromatography (eluent: DCM/MeOH 99:1 to 95:5) (7 mg, free base)
Reaction SMILES: [OH-].[Na+:2].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[O:12].Cl>O>[OH:9][C:3]1[CH:8]=[CH:7][C:6]([CH:11]([OH:12])[C:10]([O-:14])=[O:13])=[CH:5][CH:4]=1.[Na+:2]
Reactant: O=CC(=O)O
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (50% w/w, ca 650 ml) was added dropwise over about one hour to a stirred mixture of phenol (1.098 kg), aqueous glyoxylic acid (50% w/w solution, 720 ml) and water (3 l) at 15° C. until a pH of 10.5 had been reached. The reaction mixture was then stirred and tested at 35° C. for 3 hours. The solution was adjusted to pH7 with concentrated hydrochloric acid and extracted at 35° C. with methyl isobutyl ketone to remove excess phenol. The aqueous solution was adjusted to pH2 with concentrated hydrochloric acid and continuously extracted in a counter-current extractor with ethyl acetate at an organic to aqueous flow rate of 1 to 1.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][N:8]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc(OC)c1OC
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with N2 inlet, a 10-mL addition funnel and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4,5-trimethoxybenzoyl chloride (0.92 g, 3.92 mmol) in CH2Cl2 (5 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered, and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf =0.34) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 1.02 g (79.1%) of off-white solid (35); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2985, 2955, 2910, 2890, 2780 (C--H), 1620 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3H, CH3, J=6.5 Hz), 1.09 (d, 3H, CH3, J=6.7 Hz), 1.64-1.79 [m, 3H, H(5) and H(9)], 2.05 [bs, 1H, H(1)], 2.44 [bd, 1H, H(4)ax, J=10.6 Hz], 2.57 [bd, 1H, H(6)ax, J=10.8 Hz], 2.66 [heptet, 1H, CH(CH3)2, J=6.6 Hz], 2.71 [bd, 1H, H(6)eq, J=11.0 Hz], 3.02-3.07 [m, 2H, H(4)eq and H(2)ax ], 3.31 [bd, 1H, H(8)ax, J=13.2 Hz], 3.80-3.92 [m, 10H, H(8)eq and OCH3 ], 4.77 [bd, 1H, H(2)eq, J=13.5 Hz], 7.29 (s, 2H, Ar--H); 13C NMR (DCCl3) ppm 15.87, 19.42 (CH3), 29.02 [C(1)], 29.78 [C(5)], 32.35 [C(9)], 46.64 [C(2)], 51.73 [C(4)], 52.48 [C(8)], 54.39 [CH(CH3)2 ], 54.95 [C(6)], 56.13, 60.86 (OCH3), 103.83, 133.32, 133.21, 138.22, 153.21 (Ar--C), 169.66 (C=O). Anal. Calcd. for C20H30N 2 O4 : C, 66.27; H, 8.34. Found: C, 66.04; H, 8.32.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)[C:11]3[CH:16]=CC=CC=3)[S:9][C:5]=2[CH:4]=1.NCC[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][CH2:11][CH2:16][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[S:9][C:5]=2[CH:4]=1
Reactant: NCCN1CCCCC1
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2sc(=NCCN3CCCCC3)sc2c1

Procedure:
A solution of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (8.39g), N-(2-aminoethyl)piperidine (2.56g) and anhydrous sodium carbonate (1.06g) in 200 ml of anhydrous dimethylformamide is heated at 120° C under a nitrogen atmosphere for three hours. The reaction mixture is poured into 1000 ml of water and extracted with three 300 ml portions of dichloromethane. The combined organic extracts are washed with two 500 ml portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield an oil. This oil is chromatographed on silica gel (1000 ml) eluting with (1) pentane (1000 ml), (2) chloroform (1000 ml), and finally methanol/chloroform (1:4, 2000 ml). The solid product from elution (3) is recrystallized from pentane to yield 4g of the title compound, melting point 42-44° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(Cl)Cl.CO.N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:31][CH3:30])=[N:37][CH:36]=4)[N:6]([CH:7]4[CH2:9][CH2:8]4)[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: Cn1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Reactant: COc1ncc(B(O)O)cn1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(-c2cc3c(n2C2CC2)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cn1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 240 but using 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-cyclopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 243.1) and (2-methoxypyrimidin-5-yl)boronic acid. tR: 0.97 min (LC-MS 6); ESI-MS: 522.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH/NH3 94:5:1): Rf=0.38; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.40 (m, 1 H) 0.60-0.85 (m, 2 H) 1.09-1.19 (m, 1 H) 3.10-3.20 (m, 1 H) 3.42 (s, 3 H) 3.92 (s, 3 H) 6.33 (s, 1 H) 6.62 (s, 1 H) 7.32 (m, J=8.60 Hz, 2 H) 7.40 (m, J=8.60 Hz, 2 H) 7.80-7.97 (m, 2 H) 8.81 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[N:13][C:12]=2[NH:11][N:10]=1.C=O.[CH:41](O)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH3:41])[CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: O=CO
Reactant: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCNCC1
Agent: C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCN(C)CC1
Temperature: 110 °C
Yield: 23 %

Procedure:
To 4-{1-methyl-8-(methyloxy)-9-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrogen trifluoroacetate (47 mg, 0.11 mmol) was added 37% aqueous formaldehyde (10 μL) and formic acid (150 μL). The mixture was heated to 110° C. for 1.5 h before cooling to rt. The mixture was diluted with a 1:1 mixture of water:acetonitrile and purified by preparative HPLC. The fractions containing desired product were combined, concentrated, and lyophilized to provide 4-(1-methyl-8-(methyloxy)-9-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol trifluoroacetate (14.1 mg, 0.026 mmol, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ9.93 (br m, 2H), 7.87 (d, 1H), 7.48 (d, 2H), 7.44 (d, 1H), 6.96 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 3.00-2.96 (q, 2H), 2.83 (s, 3H), 2.74 (d, 3 h), 2.18 (m, 1H), 2.09 (br d, 2H), 1.61-1.52 (m, 2H); MS (EI) for C25H28N4O3: 433 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]4[O:23][CH2:24][O:25][C:18]=34)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[OH2:26].[CH3:27]O.C[O-].[Na+]>>[CH3:27][O:26][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]4[O:23][CH2:24][O:25][C:18]=34)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Brc1cccc(CN2CCC(CCc3cccc4c3OCO4)CC2)n1
Reactant: O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(CN2CCC(CCc3cccc4c3OCO4)CC2)n1

Procedure:
In a 28% sodium methoxide methanol solution (2 ml) was dissolved 218 mg of 1-[(6-bromo-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine obtained in Referential Example 19, followed by heating under reflux for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 144 mg of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@@H:22]1[C@@H:21]([N:11]2[C:10](=[O:28])[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]4=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:30][CH:29]=4)[CH:8]=3)[N:13]=[CH:12]2)[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: C1COCCN1
Reactant: O=c1c2cc(Cc3ccc(Cl)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 65 °C

Procedure:
To a solution of 6-(4-chlorobenzyl)-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.238 mmol) in 2 mL of DMF under an atmosphere of nitrogen was added morpholine (0.083 g, 0.95 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.012 g, 0.024 mmol), cesium carbonate (0.232 g, 0.713 mmol), and 0.2 mL of water. The mixture was warmed to 65° C. for 5 min, flushed with nitrogen, and irradiated in a microwave reactor at 130° C. for 25 min. The reaction was cooled to rt and diluted with water and dichloromethane. The aqueous layer was reextracted with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-4% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 471.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.30 (s, 1H), 8.01-7.98 (m, 2H), 7.65-7.59 (m, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.89-4.82 (m, 1H), 4.35 (s, 2H), 4.22-4.18 (m, 1H), 4.13-4.08 (m, 2H), 3.79 (t, J=4.8 Hz, 4H), 3.59-3.52 (m, 1H), 3.34-3.28 (m, 1H), 3.06 (t, J=4.8 Hz, 4H), 2.66 (br s, 1H), 2.32-2.22 (m, 1H), 2.03-1.99 (m, 1H).
Reaction SMILES: [CH3:1]CN(CC)CC.[CH3:8][C:9]([O:11][C:12]([CH3:14])=[O:13])=O.OC1C=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=O)=[CH:18][CH:17]=1>C(Cl)Cl>[C:12]([O:11][C:9]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[CH2:1])=[CH:20][CH:8]=1)(=[O:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(O)cc3)cc2)CC1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=C(Nc1ccc(OC(C)=O)cc1)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
1.1 eq of Et3N and 2 eq of Ac2O were added to a solution of tert-butyl 4-(4-{[(4-hydroxyphenyl)amino]carbonyl}phenyl)piperazine-1-carboxylate in dry DCM (0.1 M) (prepared as described in published International patent application WO98/00134) and the solution stirred at RT for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with DCM and the organic phase was washed with aqueous HCl (1N) (twice), saturated aqueous NaHCO3 and then brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound as a white solid (90%); MS (ES+) m/z 440 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:4]([CH2:9][CH2:10][CH3:11])[C:5]([O:8][CH2:22][O:23][CH3:24])=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CCCc1c(O)ccc(Br)c1COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-propyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenol (972 mg, 2.95 mmol) in N,N-dimethylformamide (5 mL), sodium hydride (55% in oil, 257 mg, 5.90 mmol) and chloromethyl methyl ether (475 mg, 5.90 mmol) were added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (910 mg, 83%) was obtained as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])/[C:29](=[N:31]/O)/[NH2:30]>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([C:29]2[N:31]=[C:7]([CH:4]3[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]3)[O:9][N:30]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2noc(C3CCC(=O)C3)n2)cc1Cl
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a slurry of 3-oxocyclopentanecarboxylic acid (0.123 g, 0.962 mmol) in DMF (1.0 ml) was added EDC (0.184 g, 0.962 mmol) followed by HOBT hydrate (0.130 g, 0.962 mmol). After about 1 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.2 g, 0.875 mmol) in DMF (0.5 ml) was added and the reaction mixture was heated to about 140° C. for about 45 min. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0.156 g, 56%) as a yellow oil. LCMS (Table 1, Method c) Rt=2.75 min, m/z 321 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
The 2-pentafluoroethoxyphenylsulfonamide obtained in Example 4b is suspended in 400 ml of methylene chloride. Then 16.3 g of methyl isocyanate are added and 28.2 g of triethylamine are subsequently added dropwise over 15 minutes to form a clear solution. The solution is evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-(2-pentafluoroethoxyphenylsulfonyl)-N'-methylurea with a melting point of 177°-179° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 74.6 g.