Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[C:8]([O:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[CH:9][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[C:8]([O:17][C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])=[CH:9][C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1

Procedure:
A mixture of 1-chloropropan-2-one (1.01 g, 11 mmol), 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)thiourea (3.24 g, 9.0 mmol), triethylamine (1.41 g, 14 mmol) and ethanol (15 mL) is heated at reflux for 16 hours. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried and concentrated. The residue is purified via chromatography to afford N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:28]=[N:29][CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]2=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:28]=[N:29][CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: COc1cnnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4ccccc4F)nc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnnc(-c2c[nH]c3ccc(-c4ccccc4F)nc23)c1
Temperature: 85 °C
Yield: 55.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-(5-methoxypyridazin-3-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridine (16 mg, 0.034 mmol) and NaOH (0.3 mL, 0.300 mmol, 1M) in THF (1 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 85° C. for 20 min. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated. The residue was purified with prep-TLC (eluting with 10% MeOH in DCM) to give 5-(2-fluorophenyl)-3-(5-methoxypyridazin-3-yl)-1H-pyrrolo[3,2-b]pyridine (6.0 mg, 0.019 mmol, 55.6% yield) as a light brown solid. MS (ESI, pos. ion) m/z: 321.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1 H, br. s.), 8.83 (2 H, s), 8.60 (1 H, s), 8.12 (1H, td, J=8.0, 1.7 Hz), 8.03 (1 H, d, J=8.6 Hz), 7.70 (1 H, dd, J=8.5, 2.1 Hz), 7.43-7.53 (1 H, m), 7.30-7.42 (2 H, m), 4.01 (3 H, s)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:17]([CH2:26][CH3:27])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH2:26][CH3:27])[N:18]([CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH3:36])=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(CCCNC(C)=O)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 24.8 %

Procedure:
7-(3-Aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and acetic anhydride (153 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0° C. and the reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×20 mL). The combined organic fractions were sequentially dried (MgSO4), filtered and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-15% CMA over 2000 mL followed by 15-20% CMA over 500 mL). The desired product was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane). A final recrystallization from acetonitrile provided 142 mg of N-{3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}acetamide as a white solid, mp 209-211° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([O:15][C:13]([CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3 g of p-hydroxyphenylacetonitrile, 3.6 ml of t-butyl bromoacetate, 6.5 g of potassium carbonate in 45 ml of dimethylformamide is stirred at room temperature for 16 hours. After dilution with water the product is extracted with ether. The ethyl layer is washed with 1N sodium hydroxide, dried over magnesium sulfate and the solvent removed in vacuo to yield p-(t-butoxycarbonylmethoxy)-phenylacetonitrile which is reduced to p-(t-butoxycarbonylmethoxy)-2-phenethylamine with sodium borohydride/cobalt chloride as described for the starting material under (g).
Reaction SMILES: [O:1]=[C:2]1[C:25]2[C:6]3=[C:7]([CH:22]=[CH:23][CH:24]=2)[NH:8][C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][C:14]=2[C:5]3=[N:4][NH:3]1.[ClH:26]>O1CCOCC1>[ClH:26].[N:4]1[NH:3][C:2](=[O:1])[C:25]2[C:6]3[C:5]=1[C:14]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]=1[NH:8][C:7]=3[CH:22]=[CH:23][CH:24]=2
Reactant: CC(C)(C)OC(=O)N1CCC2=C(C1)Nc1cccc3c(=O)[nH]nc2c13
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2CCNC1
Yield: 57 %

Procedure:
To a solution of tert-butyl 3-oxo-7,8,10,11-tetrahydro-2H-phthalazino[8,1-bc][1,7]naphthyridine-9(3H)-carboxylate (100 mg) in dioxane (6 mL) was added con.HCl (2.0 mL) dropwise, the mixture was then stirred at room temperature for 0.5 h. The solvent was evaporated in vacuo and water (10 mL) was added. The mixture was washed with methylene dichloride (20 mL), and the aqueous phase was evaporated to afford 8,9,10,11-tetrahydro-2H-phthalazino[8,1-bc][1,7]naphthyridin-3(7H)-one hydrochloride (46 mg, 57%). 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.95 (s, 1H), 9.59 (s, 1H), 7.34-7.69 (m, 3H), 3.33-3.51 (m, 4H), 2.55-2.56 (m, 2H). MS (ESI) m/e [M+1]+241.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:38]2)=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:15][O:14][N:13]=2)=[S:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)[Si](OCc1nonc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 78.5 %

Procedure:
Into a round bottom flask was placed a solution of N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carboxamide (4.1 g, 9.5 mmol) in anhydrous toluene (79 mL) under N2. 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (7.7 g, 19 mmol) was added while stirring at ambient temperature. After addition, the resulting suspension was stirred and heated at 100° C. for 20 hrs. A considerable amount of solid precipitate was filtered off while the reaction was still hot, which was residual Lawesson's reagent. The liquid was then concentrated to give a yellow oil which was dissolved in chloroform and loaded onto a 330 g silica column eluting with 25% ethyl acetate/hexane to yield the desired product (3.31 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ: 12.87 (s, 1H), 7.8 (ddd, J=8.9, 4.3, 2.7 Hz, 1H), 8.21 (dd, J=6.8, 2.7 Hz, 1H) 7.55 (dd, J=9.0, 9.0 Hz, 1H), 5.14 (s, 2H), 1.07 (m, 3H), 0.97 (d, J=7.0, 18H); (M+H)+: m/z=444.134.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][Sn](C)(C)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:23][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: C[Sn](C)(C)C
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 120 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.07 mmol, 0.15 equiv) and tetramethyltin (270 μL, 1.91 mmol, 4.0 equiv) were combined in 5 mL of a 1:1 solution of DMF:HMPA. The solution was degassed and heated to 120° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O4S (M+H+): 324.1013. Found 324.1014.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH2:35]N=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(O)C>CN(C=O)C>[CH2:34]([O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
In DMF (50.0 ml), 5-t-butoxycarbonylamino-(2S)-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanoic acid (2.50 g) was dissolved. The solution was added with WSCI hydrochloride (1.21 g) and HOBt (0.84 g) and the whole was stirred at room temperature for 1.5 hours. The solution was added with ethanol (1.0 ml) and the whole was stirred at room temperature for additional 17 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.22 g) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)(=O)=O)=CC=1.[N:17]1([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[K+]>CN(C=O)C.O>[C:26]([O:25][C:24](=[O:30])[NH:23][N:17]1[CH2:22][CH2:21][N:20]([CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH2:19][CH2:18]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NN1CCN(CC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of (2-methyl-2-oxiranylmethyl) toluene-4-sufonate (9.75 g, 40.3 mmol), tert-butyl piperazin-1-yl-carbamate (6.75 g, 33.5 mmol) prepared in Reference Example 36, triethylamine (7 ml, 50.3 mmol) and potassium iodide (6.68 g, 33.5 mmol) in DMF (70 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=4/1) to afford tert-butyl[4-(2-methyl-2-oxiranylmethyl)piperazin-1-yl]carbamate (4.66 g, yield 51%) as a colorless crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(O)cc1

Procedure:
A mixture of 10 g 4-hydroxycinnamic acid, 100 ml ethanol and 0.5 ml concentrated sulphuric acid was heated under gentle reflux for 96 hours. The reaction mixture was poured onto water, the resultant precipitate filtered off, washed with portions of water and then dried. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent and recrystallisation from acetonitrile to yield 9.2 g of ethyl (E)-4-hydroxycinnamate.
Reaction SMILES: Cl.[NH2:2][OH:3].[O:4]=[C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][C:17]([CH:19]=O)=[CH:18][C:6]1=2>N1C=CC=CC=1>[O:4]=[C:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][C:17]([CH:19]=[N:2][OH:3])=[CH:18][C:6]1=2
Reactant: O=Cc1ccc2oc3ncccc3c(=O)c2c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=c1c2cc(C=NO)ccc2oc2ncccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
11 g of hydroxylamine hydrochloride is added to a suspension of 30 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde in 600 ml of pyridine, and the mixture is vigorously stirred at 80°C for 1 hour. After cooling, the crystals are filtered off, washed with water, and dried to give crude 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carbaldehyde oxime melting at 254°-256°C with decomposition.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:34]=[C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=1)[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:30](OC)=[O:31])=[CH:20]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:38]([O:37][C:35]1[CH:34]=[C:17]([CH:16]=[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:36]=1)[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:30][OH:31])=[CH:20]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Lithium aluminium hydride (1.97 g) was added to a solution of methyl 1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolecarboxylate (26.2 g) in tetrahydrofuran (250 ml) at 0° C., and the mixture was stirred at room temperature for one hour. Sodium sulfate decahydrate (16.1 g) and hexane (250 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The colorless crystals obtained were collected by filtration to yield [1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (24.20 g, yield: 98%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 115–116° C.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[C:4](=[O:11])O1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(N(CC)C(C)C)(C)C>[CH2:13]([NH:17][C:4](=[O:11])[C:5]([CH3:9])([CH3:10])[C:6]([OH:7])=[O:8])[CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)OC(=O)C(C)(C)C(=O)O1
Reactant: CCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)C(C)(C)C(=O)O
Yield: 60 %

Procedure:
1.72 g (10 mmol) —2,2,5,5-Tetramethyl-[1,3]dioxane-4,6-dione and 1.02 ml butylamine were stirred in 7 ml N,N-diisopropyl-ethylamine for 18 hours at room temperature. The excess N,N-diisopropyl-ethylamine was decanted and the residue was extracted with 1N aqueous hydrochloric acid/ethylacetate. The ethylacetate phase was washed with 1N aqueous hydrochloric acid, brine and was dried over sodiumsulfate. Evaporation of the solvent and recrystallisation from dichloromethane/heptane yielded 60% N-butyl-2,2-dimethyl-malonamic acid as white solid, MS m/e (%): 188.4 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(Cc4ccccc4)CC3)cc21
Yield: 51.7 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.7 g (0.005 mole), benzylchloride 1.26 g (0.01 mole), triethylamine (0.01 mole) and DMF 10 ml was heated at 90°-100° C. for 7 hours under stirring. After cooling, the reaction mixture was dried up under vacuum. The residue was dissolved in CHCl3, washed with water, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.1 g (52%) of 1-ethyl-6-chloro-7-(4-benzyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless prism.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C(O)(=O)/C=C\C(O)=O.[NH2:17][C:18]1[N:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23]2[C:19]=1[NH:20][C:21](=[O:45])[N:22]2[CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:67]([C:69]1[CH:74]=[CH:73][C:72]([CH2:75][C:76]([O:78][CH3:79])=[O:77])=[CH:71][CH:70]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1.O>[NH2:17][C:18]1[N:26]=[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23]2[C:19]=1[NH:20][C:21](=[O:45])[N:22]2[CH2:32][CH2:33][CH2:34][N:35]([CH2:67][C:69]1[CH:70]=[CH:71][C:72]([CH2:75][C:76]([O:78][CH3:79])=[O:77])=[CH:73][CH:74]=1)[CH2:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCCCC3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCCCC3)Cc3ccc(CC(=O)OC)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-amino-2-butoxy-9-{3-[(3-piperidin-1-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one dimaleate (20.0 g, 31.3 mmol), triethylamine (9.5 g, 94.1 mmol) and NMP (72 g) was stirred at 25° C. for 30 min. Sodium triacetoxyborohydride (11.3 g, 53.3 mmol) was added to the solution and stirred for 15 min. A solution of methyl (4-formylphenyl)acetate (8.4 g, 47.1 mmol) in NMP (10.3 g g) was added to the solution and the mixture stirred for 8 hr. Then NMP (41 g) was poured into the reaction solution and cooled to 5° C. To the solution was added cold water (200 g) dropwise and the mixture stirred. The reaction mixture was adjusted to pH9 by using 10% aqueous Na2CO3 and water (86 g) added. After stirring for 1 hr, the reaction mixture was filtered, the collecting solid washed with cooled water and dried to give the crude subtitle compound as a white solid. Yield 15.0 g, 84%.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=4)[C:23]=3[CH3:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([N:22]2[C:23]([CH3:24])=[C:19]([CH2:18][O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])[CH:9]=[CH:10]4)[CH:20]=[N:21]2)[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: CCOC(=O)C(C)(C)n1ccc2cc(OCc3cnn(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(COc2ccc3c(ccn3C(C)(C)C(=O)O)c2)cnn1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
2-{5-[1-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-1H-pyrazol-4-ylmethoxy]-indol-1-yl}-2-methyl-propionic acid ethyl ester from step A in ethanol (2 mL) is added NaOH (5.0 M, 1 mL). After heated at 50° C. for 2 hrs, ethanol is evaporated. The residue is diluted with water, acidified with 5 N HCl, extracted with ether, dried over sodium sulfate. Concentration and purification by reversed phase HPLC (acetone/water/TFA as eluents) yields the title compound (60 mg). MS (ES): 525.96(M+−1); the structure is also confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([CH3:31])[C:19]=1[CH3:32]>>[Cl:1][C:2]1[C:6]([CH2:7][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH3:31])[C:19]=2[CH3:32])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: COc1ccc(-c2snc(Cl)c2CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Step 6 and 7 by coupling of 3-chloro-4-(chloromethyl)-5-(4-methoxyphenyl)-1,2-thiazole and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR: (300 MHz, CDCl3) δ: 7.502 (d, J=6.6 Hz, 2H), 7.00 (t, J=6.0 Hz, 3H), 6.784 (d, J=6.0 Hz, 1H), 4.925 (s, 2H), 3.87 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H22ClNO4S, 430.1 (M−H). found 430.1.