Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[H-].[Na+].[CH3:7][N:8]([CH3:21])[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C@H:11]([OH:20])[CH2:10]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1>Cl>[CH3:7][N:8]([CH3:21])[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C@H:11]([O:20][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:10]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Reactant: Fc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.6 ml of dimethylsulfoxide and 60 mg of sodium hydride in the form of a 50% oil dispersion was heated at 60° C. for 25 minutes and was then cooled to 25° C. after which 205 mg of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto. After 15 minutes, 0.4 ml of p-difluorobenzene were added thereto and the mixture was heated at 90° C. for 63/4 hours and was then cooled to 20° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 350 mg of raw product which was dissolved in 10 ml of N hydrochloric acid. The solution was washed with ether and made alkaline with sodium hydroxide solution. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 270 mg of cis N,N-dimethyl-5-[4-fluorophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an oil.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([F:30])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:30][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (14.5 mg, 0.0727 mmol), (3R)-1-[7-(1-aminoethyl)-5-fluoroquinolin-8-yl]pyrrolidin-3-ol (10 mg, 0.04 mmol), and N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) in isopropyl alcohol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. First peak retention time 1.32 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2. Second peak retention time 1.40 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][CH:15]([F:18])[CH2:16]I.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][CH:15]([F:18])[CH2:16][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: FC(F)CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC(F)F)C1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg), 1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.403 mL) and the reaction stirred for 72 hours at 70° C. The reaction mixture was concentrated and the crude product was purified on a silica gel and was eluted with a 0, 2, and 5% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:22]N(C)CCO.C[Zn]C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:22][C:2]1[N:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Agent: C[Zn]C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
A mixture of 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (Example 128) (0.1 g, 0.28 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (61.5 mg, 84.0 μmol) and N,N-dimethylethanolamine (14.1 μL, 140 μmol) in tetrahydrofuran (1.5 mL) under argon was treated with 1.2M dimethylzinc in toluene (280 μL, 0.33 mmol). The reaction mixture was stirred in a sealed vial at 50° C. overnight. At this time, the reaction was treated with additional dimethylzinc (0.14 mL). The reaction mixture was stirred at 50° C. over the weekend. At this time, the reaction mixture was cooled to room temperature, quenched with a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. Methanol (0.5 mL) was added, the mixture was filtered and the layers were separated. The organic layers were absorbed onto silica gel. Flash chromatography (12 g silica column, 0-40% ethyl acetate/hexanes) followed by trituration with methylene chloride afforded 6-methyl-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (14 mg, 17%) as white solid. 1H NMR (methanol-d4) δ ppm 7.76-7.86 (m, 4H), 7.69 (s, 1H), 7.28 (s, 1H), 6.95, (s, 1H), 2.28 (s, 3H). LC-MS calcd. for C15H12F3N2O [(M+H)+] 293, obsd. 293.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])=[CH:4][CH:3]=1.[CH2:16](I)[CH3:17]>C(O)C>[CH2:16]([S:15][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12](=[O:13])[CH2:11][N:10]=1)[CH3:17]
Reactant: CCI
Reactant: NC(=O)CNC(=S)Nc1ccc(F)cc1
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccc(F)cc1
Yield: 29.9 %

Procedure:
A mixture of 2-[3-(4-fluorophenyl)-thioureido]-acetamide (9.1 g) and ethyl iodide (12.5 g) was heated at reflux in ethanol (200 mL) for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) then washed with water. The organic phase was extracted with 2N HCl (2×400 mL). The acid extract was made basic with 5% sodium bicarbonate solution. The precipitate was collected by filtration and dried. Crystallization from diethyl ether afforded the title compound (2.85 g) as an off-white solid, m.p. 114°-115° C. Anal. Calcd. for. C11H11F N2O S: C, 55.45; H, 4.65; N, 11.76. Found: C, 55.17; H, 4.54; N, 11.81. Mass spectrum (EI, M.+) m/z 238. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.32-7.39 (m, 4H), 4.30 (s, 2H), 3.07 (q, 2H), and 1.28 ppm (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38]C(C)(C)C)=[O:37]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([CH2:35][C:36]([OH:38])=[O:37])[C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1=NN(Cc2ccccc2)C(=O)C(C)(C)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C2=NN(Cc3ccccc3)C(=O)C(C)(C)C2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 80 °C

Procedure:
The product of step b) (˜0.3 mmol) was dissolved in 5 mL DMF and treated with K2CO3 (1 mmol, 138 mg) and t-butyl bromoacetate (1 mmol, 195 mg). After heating to 80° C. for ½ h, the reaction was cooled, diluted with EtOAc and washed 5× water. The reaction was concentrated, dissolved in EtOH (5 mL) and treated with 1.4 mL of 1M NaOH. After heating to 80° C. for ½ h, the reaction was acidified with 3 M HCl and extracted into DCM (3×).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([N:36]1[CH2:37][CH2:38][N:33]([C:30]2[CH:31]=[CH:32][C:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:47])[CH3:46]
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in dichloromethane (2 mL) was added pyridine (23 μL, 0.28 mmol) followed by acetyl chloride (17 μL, 0.24 mmol). The mixture was stirred (rt) overnight. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (20 mL), brine, and was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 28 mg (26%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.97 (d, 2 H), 7.94 (s, 1 H), 7.81 (d, 1 H), 7.66-7.64 (m, 1 H), 7.36-7.26 (m, 5 H), 7.19 (dd, 1 H), 7.06-7.01 (m, 3 H), 5.66 (s, 2. H), 3.62-3.55 (m, 4 H), 3.26-3.21 (m, 2 H), 3.20-3.14 (m, 2 H), 2.05 (s, 3 H); ES-MS m/z 543.33 [M+H]+, HPLC RT (min) 2.65.
Reaction SMILES: NC(N)CCCCCC(OC[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCCCCCN
Reactant: NC(N)CCCCCC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=Cc1ccccc1
Solvent: ClCCl
Product: NCCCCCCNc1ccccc1
Yield: 100 %

Procedure:
To prepare 1-amino-6-phenylmethoxycarbonyl-amino-hexane (23), an equimolar mixture (0.01 mol) of 1,6-diaminohexane and benzaldehyde in 25 mL of methylene chloride was stirred for 5 hr in the presence of 1.5 g of anhydrous magnesium sulfate at room temperature. After removing the drying agent by filtration the filtrate was evaporated to dryness under reduced pressure to give 2 g (100% yield) of crude 1-amino-6-phenylamino-hexane 22 as a colorless oil; NMR(CDCl3) 1.1-1.9(m, 10H, hexane CH2 -2,-3,4,-5, NH2); 2.6(m, 2H, CH2 -1); 3.51(m, 2H, hexane CH2 -6); 7.1-7.8 (m, 5H, aromatic); 8.16(s, 1H, imine CH). To a mixture of 2 g (0.01 mol) of 22 and 1.4 mL (0.01 mol) of triethylamine in 20 mL of methylene chloride. Then 1.78 g (0.01 mol) of benzylchloroformate was added dropwise at -5° C. The resulting mixture was stirred for 0.5 hr at 0° C. and for 2 hr at room temperature then diluted to 50 mL with methylene chloride and washed with water (20 ml), 2% sodium bicarbonate (20 ml), water and saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of solvent under reduced pressure the residue was dissolved in 5 mL of ethanol and 10 mL of 2N hydrochloric acid was added. The resulting mixture was stirred for 6 hr at room temperature then evaporated to dryness under reduced pressure. The residue was diluted to 50 mL with water and washed with ethyl ether (2 × 15 ml). The water phase was evaporated under reduced pressure and the product 23 was purified by crystallization from a small portion of water with a yield of 42%; mp 175°-178° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:11]OC(OC)N(C)C.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:11]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH:2]([CH3:10])[CH3:1])=[N:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COC(=O)c1cn(-c2ccc(OC)cc2)nc1C(C)C
Yield: 51 %

Procedure:
Using methyl 4-methyl-3-oxopentanoate (3.6 g), dimethylformamide dimethylacetal (3.5 mL) and p-methoxyphenylhydrazine monohydrochloride (4.5 g) and in the same manner as in Example 15(1), the title object compound (3.5 g, 51%) was obtained as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
15.6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate of melting point 106°-107° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=C)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.O.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=[O:24])[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O
Reaction time: 60 h

Procedure:
1.00 g (3.25 mmol) of the compound from Example 214A and 217 mg of OsEnCat 40 (micro-encapsulated osmium tetroxide, 0.3 mmol/g, 65 μmol) are placed in 20 ml dioxan and 9 ml water and slowly treated with 2.09 g (9.8 mmol) of sodium periodate at RT. This is allowed to react with vigorous stirring (1-4 days) until HPLC testing of the mixture shows adequate conversion. For the workup, the osmium catalyst is removed by filtration, then washed with dioxan and the total filtrate freed from the organic solvents on the rotary evaporator. The aqueous residue is diluted with more water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent removed on the rotary evaporator. The oily residue is dried under high vacuum. 948 mg (purity ca. 84%, 79% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][CH2:13]Cl)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:21])[CH:8]=2)[N:3]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24].O>CN(C)C=O>[ClH:1].[CH2:22]([N:25]1[C:2]2=[N:3][C:4]3[C:9]([CH:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]2[CH2:12][CH2:13]1)=[CH:8][C:7]([Cl:21])=[CH:6][CH:5]=3)[CH2:23][CH3:24]
Reactant: ClCCN1C(Cl)=Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: CCCN
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCN2C1=Nc1ccc(Cl)cc1C2c1ccccc1
Product: Cl
Temperature: 105 °C
Yield: 66.2 %

Procedure:
A mixture of 3.21 g of 3-(2-chloroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone and 10 g of phosphorus oxychloride was heated with stirring at 105° C. for 20 hours. The resulting solution was evaporated in vacuo to dryness and the resulting residue was dissolved in chloroform. The chloroform solution was washed with an aqueous sodium bicarbonate solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline. The crude solid was chromatographed on silica gel using chloroform as an eluting solvent. Removal of the solvent and recrystallization of the residue from a mixture of benzene and petroleum benzin gave 0.60 g of pure product, m.p. 169°-170° C. To a solution of 0.34 g of 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline in 2 ml of dimethylformamide was added 0.59 g of n-propylamine and the mixture was heated at 105° C. for 5 hours. After cooling, 10 ml of water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using chloroform as an eluting solvent to give 0.24 g of 1-(n-propyl)-5-phenyl-7-chloro-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazoline hydrochloride. Recrystallization from a mixture of ethanol and diisopropyl ether gave slightly brown fine crystals, m.p. 258° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25])([O-:20])=[O:19].[OH-].[Na+]>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:25][C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(F)cc1

Procedure:
Ethyl 5-(4-fluorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(4-fluorophenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]1([CH2:13][CH2:14][OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC[O:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:7]1([CH2:13][CH2:14][O:15][C:1](=[O:5])[C:2]([O:18][CH2:19][CH2:20][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCc1ccccc1)C(=O)OCCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
Oxalyl chloride (10.2 g, 80.4 mmol) was added dropwise during 20 min to a stirred solution of 2-phenylethanol (20.0 g, 163.7 mmol) in pyridine (165 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. Ether was added (300 mL, 2×) and the mixture extracted with H2SO4 (10%, 300 mL, 3×), a saturated solution of NaHCO3 (300 mL, 3×) and a saturated solution of NaCl (300 mL, 2×, pH 6). The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/diethyl ether 1:1) gave 20.1 g (84%) of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O.C(OCC)(=O)C>CC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25 mmol) was dissolved in anhydrous acetone (75 ml) and added N-iodo succinimide (6.18 g, 27.5 mmol) under nitrogen atmosphere and stirred at RT for 2 h. The reaction was monitored by TLC (10% Ethyl acetate in hexane). The reaction mixture was cooled to RT and filtered, washed with cold acetone (50 ml) and dried under vacuum to afford 7.05 g (87% yield) of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:11]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])=[C:4]([F:26])[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=2[F:26])[CH:20]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCC(=O)O)c(C(=O)NCc2ccc(Br)cc2F)c1
Yield: 72.1 %

Procedure:
[2-(4-Bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid (1.10 g, 2.76 mmol) was dissolved in ethyl alcohol (40 mL, 0.1 M), treated with 10% Pd on carbon (Degussa, 0.10 g) and placed under a balloon of hydrogen for 12 h. The reaction was filtered through Celite and concentrated to give a crude solid which was recrystallized from heptane and ethyl acetate to give [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid (0.79 g, 66%): mp 204° C (dec.); Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.16 (br t, J=6.3 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.46-7.11 (m, 5H), 4.91 (s, 2H), 4.57 (br d, J=3.6 Hz, 2H). ESI-LC/MS m/z calcd for C16H14BrFN2O4: 396.0 found 395.0 (M−1)−. Anal. calcd for C16H14BrFN2O4: C, 48.38; H, 3.55; N, 7.05. Found C, 48.05; H, 4.02; N, 6.94.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[NH:27][C@H:26]([C:28]([NH2:30])=[O:29])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[C:23]([CH3:31])([CH3:22])[CH2:24][CH2:25][C@H:26]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC[C@@H](C(N)=O)N1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC[C@@H](C(N)=O)N1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (S)-5,5-dimethylpyrrolidine-2-carboxamide hydrochloride in the presence of TBTU and DIEA to obtain the title compound as colorless foam; MS (EI): m/e=409.5 [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:4].O=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16].S(Cl)([Cl:21])=O>C(OCC)C>[CH3:1][N:2]([CH:14]([Cl:21])[C:15]([Cl:18])([Cl:17])[Cl:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:4]
Reactant: CNC(=O)Nc1ccccc1F
Reactant: O=S(Cl)Cl
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C(=O)Nc1ccccc1F)C(Cl)C(Cl)(Cl)Cl
Reaction time: 0.08 h

Procedure:
N-methyl-N'-o-fluorophenyl urea (16.8 g, 0.1 mol) was combined with 22.5 g (0.15 mol) chloral and 18.0 g (0.15 mol) thionyl chloride. After several minutes, an exothermicity was noted and the reaction mixture became a homogenous yellow oil. After 5 minutes more, a precipitate began to form. After 1 1/2 hours, a 3:1 mixture of diethyl ether:petroleum ether was added and the product was collected of a filter and dried. The solid, which weighed 25 g, melted at 130°-141° C and analyzed as follows: %Cl, calc. 35.7, found 37.3; %N, calc. 9.5, found 9.5.