Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].CS[C:6]([S:33][CH3:34])=[CH:7][C:8]([C:10]1[N:26](C2CCCCO2)[C:13]2=[CH:14][C:15]3[C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=3[CH:20]=[C:12]2[N:11]=1)=O>C(#N)C>[CH2:21]([N:18]1[C:19]2[CH:20]=[C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[C:6]([S:33][CH3:34])[NH:3][N:2]=4)[NH:26][C:13]3=[CH:14][C:15]=2[C:16]([CH3:24])([CH3:25])[C:17]1=[O:23])[CH3:22]
Reactant: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(=O)C=C(SC)SC)n3C1CCCCO1
Reactant: NN
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4cc(SC)[nH]n4)nc3cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
Hydrazine monohydrate (0.92 g, 1.8 mmol) was added to a suspension of 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-1-(tetrahydro-pyran-2-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (0.68 g, 1.81 mmol) in acetonitrile (15 mL) and stirred for 24 h. After cooling to room temperature the precipitate was collected, washed with acetonitrile and ether to yield 0.5 g (81%) of a pale white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:3]=1.Cl[CH2:17][C:18](=O)[CH3:19].C([O-])(O)=O.[Na+]>C(O)C>[CH3:19][C:18]1[N:8]=[C:5]2[C:4]([CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:3][C:2]([CH3:1])=[N:7][N:6]2[CH:17]=1
Reactant: CC(=O)CCl
Reactant: CCCC(CCC)c1cc(C)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Temperature: 75 °C
Yield: 70.6 %

Procedure:
A 250 mL round bottom flask is charged with 6-methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine (0.611 g, 0.00295 moles, 1 equiv), ethanol 2B (30 mL), and chloroacetone (0.382 g, 0.328 ml, 0.00412 moles, 1.4 equiv). The reaction mixture is heated at 75° C. overnight and then cooled to room temp. NaHCO3 (0.371 g, 0.00442 moles, 1.5 equiv) is slowly added to the reaction mixture that is then heated to 100° C. overnight. The reaction mixture is cooled and the solvent is evaporated. Dichloromethane is added and the reaction mixture is passed through filter paper. The solvent is evaporated to obtain a brown oil which is purified via silica gel chromatography. The material is eluted with a hexanes and ethyl acetate gradient to obtain 0.511 g of the final products. Two peaks are identified in the lc/ms. The mixture is used “as is” in the next reaction. MS (APCI): 246 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([NH2:11])[CH2:6][CH2:5]2.Cl[CH2:13][C:14]1([CH:27]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:13][C:14]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH2:27]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CCl)CC1
Reactant: N[C@@H]1CCc2cc(Br)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Temperature: 50 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (1835 g, 8.66 mol) in anhydrous methanol (24 L) was added tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (2310 g, 8.83 mol). The mixture was stirred at 50° C. for 16 h, and cooled to rt. Sodium cyanoborohydride (1000 g, 15.9 mol) in THF (15 L) was added via a syringe pump over 2 hours. The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath. The reaction was cooled to 20° C. and transferred via a cannula into a vessel containing 24 L of 2.5M sodium hydroxide, and 30 L of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×5 L). The aqueous layer was treated to destruct residual sodium cyanoborohydride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude material was slurried in MTBE (7 L) by stirring at 40° C. for 1 h and at rt for 1 h. The solid was filtered, and washed with MTBE (2×500 mL) and dried under vacuum oven at 50° C. to give the title product as a white crystals (3657 g, 90%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H). [α]D20=+39.6 deg (c=1.06 mg/mL, MeOH).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:27]([O:26][C:11]1[CH2:12][CH:13]([C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[CH2:14][C:15](=[O:16])[C:10]=1[C:7](=[N:6][O:5][CH2:3][CH3:4])[CH2:8][CH3:9])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
Aqueous 1% sodium hydroxide solution (6 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (0.42 g; 1.28 mmole) in acetone (50 ml). The mixture was stirred at room temperature for a period of 5 minutes and then benzoyl chloride (0.2 g) was added dropwise. The mixture was stirred for a further period of 15 minutes and then the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product was purified by chromatography over silica gel (eluant dichloromethane) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-mesitylcyclohex-2-en-1-one (0.38 g; 68.6%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10](C3C=CN=C(SC)N=3)[C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Yield: 161.5 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with mCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:32][CH2:33][CH3:34])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:25]([N:17]([C:18]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:19])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]([CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[CH:16]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCC3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCC3)ccc2n1CC(=O)O

Procedure:
[5 -(Benzyl-cyclopentanecarbonyl-amino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.47 (d, 1H), 7.21 (m, 6H), 6.95 (m, 1H), 5.08 (s, 2H), 4.87 (s, 2H), 2.73 (t, 2H), 1.71 (m, 9H), 1.33 (m, 2H), 0.99 (t, 3H). MS calculated for C25H29N3O3+H: 420, observed: 420.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C(OCC)(=O)C>[NH2:26]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: N
Reactant: O=C(c1ccccc1)c1sc2ccc(Cl)cc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccc(Cl)cc2C1=O)c1ccccc1
Yield: 57 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-5-chloro-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 57% of theory. M.p. 172°-173° C. (ethyl acetate)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:5])[CH3:2].N.[H][H]>[Pd].CO>[CH2:1]([O:3][C:4]([N:6]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CCOC(=O)N(c1ccccc1)C1(C(=O)OC)CCNCC1

Procedure:
A solution of 16.2 parts of O4 -methyl O1 -(phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-1,4-piperidinedicarboxylate in 200 parts of methanol and 20 parts of methanol, previously saturated with ammonia is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 11.7 parts of methyl 4-[(ethoxycarbonyl)phenylamino]-4-piperidinecarboxylate as an oily residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](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>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)cc1OC
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-2-ol, 3,4-dimethoxyphenyl boronic acid (1.3 equiv.) and dichlorobis (triphenylphosphino)palladium (ii) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 M solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 M. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ol as an off-white solid (34% yield). 1H NMR (DMSO-d6): δ 11.86 (broad s, 1H), 11.67 (broad s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.89 (dd, J=2.5, 10 Hz, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.23 (dd, J=2.0, 8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.44 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H); MS: m/z 348.1 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C@@H:51]1[CH2:53][C@H:52]1[C:54](O)=O.C(N(CC)C(C)C)(C)C.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:54]([CH:52]5[CH2:53][CH:51]5[F:50])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)[C@@H]1C[C@H]1F
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C2CC2F)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (200 mg), HATU (224 mg), trans-2-fluoro-cyclopropanecarboxylic acid (100 mg), N,N-diisopropylethylamine (288 μl) and DMF (4 ml) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (4.0 ml) and stirred at 90° C. for 1 h. After AcOH was evaporated, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (25.8 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>[CH:12]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 85 °C
Yield: 92.9 %

Procedure:
A solution of 4-bromo-2-fluoronitrobenzene (0.5 g, 2.27 mmol), cyclopropylboronic acid (0.293 g, 3.41 mmol), tribasic potassium phosphate (0.965 g, 4.55 mmol), tricyclohexylphosphonium tetrafluoroborate (0.021 g, 0.057 mmol) and palladium (II) acetate (6.12 mg 0.027 mmol) in 11 mL of a toluene-water mixture 10:1 (v/v) was nitrogen purged-vacuum degassed three times. The reaction mixture was then heated in an oil bath at 85° C. for four hours. The reaction mixture was partitioned with ethyl acetate and the organic phase water washed then dried (Na2SO4) and concentrated. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to provide the title compound (0.382 g, 88%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(NC(=O)COc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NCCOc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 59.6 %

Procedure:
N1-(4-Methoxyphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (90 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 0.98 ml) was then added to the solution, and the mixture was heated under reflux for 3 hr. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (52 mg, yield 60%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:10])=[C:3](/[CH3:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OCC)C>[Cl:11][C:12]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][C:2]([CH3:10])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9])=[O:25])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C(C)=C(/C)N
Solvent: CCOCC
Product: CCOC(=O)C(C)=C(C)NC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1
Reaction time: 2 h

Procedure:
4.7 g of ethyl 3-amino-2-methylcrotonate, dissolved in 15 ml of absolute diethyl ether, are treated at 23° C. while stirring with a solution of 6.7 g of ethyl 2-chloro-5-isocyanatobenzoate and stirred for 2 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on 400 g of silica gel using diethyl ether/n-hexane (1:1) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate, m.p. 88°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]([CH2:8][CH2:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:6]2[CH2:8][CH2:9][C@H:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[O:21]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C(=O)CCC(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CC[C@H](c3ccc(OC)c(OC)c3)O2)cc1OC
Yield: 20.8 %

Procedure:
3.0 g of 1,2-bis(3,4-dimethoxybenzoyl)ethane was reduced with 350 mg of lithium aluminum hydride in 50 ml THF at 0° C. for 1 hour and ambient temperature for 3 hours. After the usual workup, 2.8 g of white solid diol was recovered and dissolved in 50 ml of methylene chloride. The solution at 0° C. was treated with 1.2 g of triethylamine followed by 1.2 g of methane sulfonyl chloride and stirred under N2 until the starting diol disappears by TLC. At this point, 200 ml of ether was added and the organic layer washed with water, 3N HCl, 10% NaOH, water and dried over anhydrous sodium sulfate. The residue obtained by evaporation was chromatographed to recover the major spot (silica gel, ethyl acetate-hexane 30:70). Crystallization from 50 ml methylene chloride and 100 ml of hexane evaporated to a final volume of 100 ml gave 0.6 g of trans- 2,5-bis (3,4-dimethoxyphenyl)tetrahydrofuran, NMR (CDCl3 ):δ 1.9-2.5 (4H, m, 3-H, 4-H) 3.85 and 3.90 (each s, 6H, 2×OCH3), 5.24 (2H, t, J=6.6 Hz, 2-, 5-H), and 6.8-7.0 (6H, m, ArH), m.p. 114°-115° C. The second and third crops gave 1.1 g of crystalline product which contains a mixture of cis and trans isomers. Separation of the isomers was made on Partisil-10 column using hexane (80%), ethylacetate (20%) as eluting solvent. The NMR of the cis isomer (m.p. 92°-96° C.) is shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:32]=[CH:31][C:20]3[S:21][C:22]([C:24]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]([C:24]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:25])=[CH:23][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:35])([CH3:36])[CH3:1])=[C:7]([CH3:33])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)NCC(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)NCC(=O)O)cc2c1
Yield: 80.6 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carbonyl)-amino]-acetic acid (90 mg, 0.177 mmol) is reduced using NaBH4 (13 mg, 0.354 mmol) in a reaction analogous to Example 2 to afford the title compound (73 mg, 81%).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH3:58])[CH:53]([NH:59][C:60](=[O:75])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][C:68]=4[OH:74])[S:65][CH:66]=2)[C:52]3=[O:76])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:73][C:72]1[CH:71]=[CH:70][CH:69]=[C:68]([OH:74])[C:67]=1[C:64]1[S:65][CH:66]=[C:62]([CH2:61][C:60]([NH:59][CH:53]2[C:52](=[O:76])[N:51]3[CH:54]2[S:55][CH2:56][C:57]([CH3:58])=[C:50]3[C:48]([OH:49])=[O:47])=[O:75])[N:63]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Yield: 98 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8h (169 mg, 0.276 mmol), Et3SiH (0.441 mL, 2.76 mmol), and trifluoroacetic acid (0.849 mL, 11.0 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9h (121 mg, 98%) as a white solid after crystallization from THF/hexane. mp 155° C. (dec); IR (KBr) 3500-2500 (br), 1768, 1670, 1467 cm-1 ; 1H NMR (DMSO-d6) δ1.97 (3H, s, CH3), 3.31 (1H, d, J=18.0 Hz), 3.51 (1H, d, J=18.0 Hz), 3.76 (2H, s, CH2), 5.00 (1H, d, J=4.5 Hz), 5.57 (1H, dd, J=8.0 and 4.5 Hz), 6.42 (2H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 7.41 (1H, s), 9.07 (1H, d, J=8.0 Hz, NH), 12.20 (2H, br s, OH), 13.20 (1H, br s, CO2H); FDMS m/z 448 (M+ +1); HRMS m/z Calcd for C19H18N3O6S2 (M+ +1): 448.0637, Found: 448.0607.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[OH-].[K+].[I-].[K+].Cl>CS(C)=O>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(C2CCc3cc(Oc4cccnc4)ccc3O2)cc1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-Phenylchroman-6-ol (598 mg), 3-bromopyridine (500 mg), potassium hydroxide (322 mg) and potassium iodide were placed in a flask with dry DMSO (10 ml). The reaction mixture was stirred at 120° C. for 3.5 hours. After cooling to room temperature 1M HCl-solution was added and the mixture was extracted wit dichloromethane. The combined organig extracts were washed with 1 M HCl-solution, then with water and brine and dried. 3-(2-Phenylchroman-6-yloxy)pyridine was purified by column chromatography using heptane-ethyl acetate as an eluant. 1H NMR (400 MHz, d6-CDCl3+MeOH) δ: 8.31 (s, 1H), 8.24 (dd, 1H, J 3.8, 1.9 Hz), 7.45-7.25 (m, 7H), 6.87 (d, 1H, J 8.6 Hz), 6.83 (dd, 1H, J 8.6, 2.6 Hz), 6.81 (d, 1H, J 2.6 Hz), 5.07 (dd, 1H, J 10.1, 2.3 Hz), 2.98 (m, 1H), 2.78 (m, 1H), 2.23 (m, 1H), 2.12 (m, 1H).