Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:10]([S:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:22](OCC)=[O:23].[O-][CH2:28]C.[Na+].Cl>C(O)C.CCOC(C)=O>[OH:23][CH:22]=[C:16]1[C:15]2[C:19](=[CH:20][C:12]([S:11][C:10]3[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=3)[C:4]([NH:6][CH3:28])=[O:5])=[CH:13][CH:14]=2)[NH:18][C:17]1=[O:21]
Reactant: Cc1c(Sc2ccc3c(c2)NC(=O)C3)cccc1C(N)=O
Reactant: CC[O-]
Reactant: CCOC=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 26 %

Procedure:
Methyl-3-(2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzamide (as prepared in step 1 above; 0.71 g, 0.239 mmol) and ethyl formate (0.058 mL, 0.717 mmol) were dissolved in anhydrous ethanol (0.5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.446 mL, 1.20 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH=1 with dropwise addition of 1M HCl(aq). The reaction mixture was diluted with EtOAc (15 mL) and washed with brine (3×15 mL). The combined organics were then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via flash silica gel chromatography (10% MeOH in CHCl3) affording the title compound in 26% yield (0.020 g, 0.0621 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1I
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(Br)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Add 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (268.1 g, 0.8 mol) and 4-bromophenyl boronic acid (173.5 g, 0.86 mol), to a solution of bis(tri-o-tolylphosphine)palladium (II) diacetate (7.00 g, 0.008 mole) in acetonitrile(1.9 L) within a 5000 mL, 3-neck round-bottom flask equipped with an overhead stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Add a solution of sodium carbonate (169.6 g, 1.6 mol) in water (1.3 L) and stir the reactor contents at room temperature while sweeping the headspace with nitrogen for 10 min. the reaction apparatus was then set for a nitrogen by-pass and the reaction mixture was heated to 73° C. Observe that HPLC analysis indicates substantial (>98%) consumption of 4-bromophenyl boronic acid and 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (flow rate: 1.5 mL/min; detection: 210 nm; mobile phase: isocratic 65/35 (v/v) acetonitrile/0.1% trifluoroacetic acid in water; column: Zorbax® SB-Phenyl; 4.6 mm×25 cm; 5 microns at 35 C). Cool the mixture to 23° C. and separate the phases. Extract the aqueous phase twice with methyl t-butyl ether (300 mL). Combine the organic phases and concentrate under reduced pressure to an oil. Dissolve the oil in a mixture of heptane (500 mL) and methyl t-butyl ether (500 mL). This results in separation of an immiscible water phase which is separated, extracted with methyl t-butyl ether (100 mL) and discarded. The organic phases are combined and concentrated under reduced pressure to an oil. The oil is dissolved in a mixture of heptane (500 mL) and methyl t-butyl ether (300 mL) and the solution is transferred to a flask set for atmospheric distillation at 83° C. The distillation is continued until distillation at 83° C. and atmospheric pressure stops. The resulting solution is cooled to 30° C. and is seeded with 3-(4-Bromo-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid ethyl ester, then the mixture is further cooled to 18° C. Filter the resulting suspension and wash the filter cake with heptane (3×100 mL). The resulting cake is air-dried and then transferred to a vacuum oven (40° C.) to afford the title compound (263 g, 90.4% yield). The title compound may be additionally purified as follows if desired.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([CH2:18][OH:19])[CH2:23][OH:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)CCOCc1ccccc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a cooled, stirred suspension of lithium aluminium hydride (103 g, 2.7 mol) in dry ether (2.51) under nitrogen was added ethyl 4-benzyloxy-2-ethoxycarbonyl-butanoate (362 g, 1.23 mol) over a period of 3 hours. On completion of the addition, the reaction mixture was allowed to warm to room temperature, and then heated under reflux for 1 hour. It was then re-cooled and the excess lithium aluminium hydride destroyed by dropwise addition of water (100 ml), 2M sodium hydroxide (100 ml) and water (300 ml). The reaction mixture was filtered, and the filter cake washed well with chloroform. The filtrate was dried (MgSO4), filtered, and evaporated to give 4-benzyloxy-2-hydroxymethylbutan-1-ol as a clear oil (226 g, 87%). δH (CDCl3) 1.35-2.05 (3H, m, CHCH2CH2), 3.30-3.80 (8H, m, 3×CH2O, 2×OH), 4.42 (2H, s, OCH2Ph), 7.26 (5H, s, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:23][C:22](=[O:24])[C:9]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[N:8]=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:31]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:23]([CH3:34])[C:22](=[O:24])[C:9]3([CH2:10][CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13][CH2:14]3)[N:8]=[C:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:6]=2[CH:31]=1
Reactant: CI
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCN(Cc1ccccc1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCN(Cc3ccccc3)CC2)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3.0 g (0.0069 mole) of 7-chloro-5-phenyl-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are dissolved in 25 ml of absolute dimethylformamide, and 0.3 g (0.007 mole) of sodium hydride (55-60% strength dispersion) is added at 20° C. After the mixture has been stirred for 20 minutes, it is cooled to 0° C., a solution of 1.0 g (0.0065 mole) of methyl iodide in 5 ml of absolute dimethylformamide is added dropwise and the mixture is stirred at 25° C. for 3 hours. The solvent is distilled off and the residue is purified by column chromatography over silica gel 60 (Merck). After the column has been eluted with methylene chloride/methanol (9:1), the oily base is obtained, which slowly crystallizes completely. Colorless crystals of melting point 169°-170° C.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]1.Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:12]1[S:8][CH:9]=[N:10][CH:11]=1)=[O:15]
Reactant: O=C(O)c1cncs1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cncs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (2.77 mL, 19.9 mmol) was added slowly to a mixture of commercially available thiazole-5-carboxylic acid (1.03 g, 7.98 mmol), N,O-dimethylhydroxylamine hydrochloride (0.778 g, 7.98 mmol), and EDCI (1.83 g, 9.57 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture was stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residual oil was chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:7](=O)[CH2:6][S:3](=[O:5])(=[O:4])[CH2:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].[NH2:21][C:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH:23]=1>C(O)C>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:6]3[S:3](=[O:5])(=[O:4])[CH2:2][CH2:1][C:7]=3[NH:21][C:22]3[CH2:26][CH2:25][C:24](=[O:27])[C:23]2=3)=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: NC1=CC(=O)CC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1CCS(=O)(=O)C1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(Cl)c([N+](=O)[O-])c1)C1=C(CCS1(=O)=O)N2

Procedure:
A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (171 mg, 1.28 mmol), 4-chloro-3-nitrobenzaldehyde (210 mg, 1.13 mmol) and 3-amino-2-cyclopenten-1-one (110 mg, 1.13 mmol) in ethanol (3 mL) was heated to reflux for 24 hours and cooled. The precipitate was collected, washed with ethanol, dried and recrystallized from methanol/ chloroform to provide the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][NH2:45]>C(O)(C)C.C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:45][CH3:44])[C:13]=3[C:12]([CH:20]([OH:43])[C:21]3[CH:22]=[CH:23][C:24]([N:28]([C:36]4[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:25][C:26]=3[F:27])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncnc(Cl)c34)c(F)n2)cn1
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CNc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To tert-butyl N-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (85, 75 mg, 0.12 mmol) in Isopropyl alcohol (0.80 mL) was added 2M methylamine in THF (0.6 ml). The resulting solution was stirred at 40° C. for 6 hours. The reaction was concentrated to give product (86, 70 mg, 94.2%). MS (ESI) [M+H+]+=620.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]([C:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:15](C(OC(C)(C)C)=O)[CH:14]=1)=O.[N+]([O-])([O-])=O.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([NH2:45])=[NH2+:44]>COCCO>[NH:15]1[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:13]([C:11]2[CH:10]=[CH:9][N:45]=[C:43]([NH:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:35])[N:44]=2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)C#C[Si](C)(C)C)c2cnccc21
Reactant: Cc1ccccc1NC(N)=[NH2+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: COCCO
Product: Cc1ccccc1Nc1nccc(-c2c[nH]c3ccncc23)n1

Procedure:
173 mg (1.25 mmol) of potassium carbonate are added to a solution of 171 mg (0.50 mmol) of tert-butyl 3-(3-trimethylsilylpropynoyl)pyrrolo[3,2-c]pyridine-1-carboxylate and 265 mg (1.25 mmol) of 2-methylphenylguanidinium nitrate (prepared by the method of J. L. Hughes et al., J. Med. Chem. 1975, 18, 1077-1088) in 2.5 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 18 hours. After cooling, the reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving [4-(1H-pyrrolo-[3,2-c]pyridin-3-yl)pyrimidin-2-yl]-o-tolyl-amine (“A6”) as beige crystals; ESI 303;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>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(C=O)C>[C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)(=[O:20])[CH3:19]
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CCNC2=O
Temperature: 110 °C
Yield: 78.4 %

Procedure:
To a flask charged with 1.55 g of (PPh3)2PdCl2 and 5.0 g of 6-Bromo-3,4-dihydro-2H-isoquinolin-1-one was added 25 mL of DMF. Then 9.58 g of Tributyl-(1-ethoxy-vinyl)-stannane was added and the reaction mixture was heated to 110° C. and stirred until completion of the reaction. The reaction mixture was filtered over celite and diluted with diethyl ether. After washing with saturdated ammonium carbonate, water and brine, the solutin was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting mixture dissolved in THF and treated with 3.0 M aqueous HCl to effect hydrolysis. The mixture was then partitioned between water and diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate, water, and brine and then dried over sodium sulfate. After filtration, the solution was concentrated and purified by flash chromatography to afford the 3.28 g of 6-Acetyl-3,4-dihydro-2H-isoquinolin-1-one.
Reaction SMILES: N#N.[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11](O)=[O:12])=[CH:7][CH:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]([F:17])([F:16])[C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([Cl:26])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of trans-4-(trifluoromethyl)cinnamic acid (20 mg, 0.10 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.02 mL, 0.23 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CO>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NCc1ccsc1
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2c(-c3ccc(OCCCNCc4ccsc4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, C-thiophene-3-yl-methylamine (Table No. 1, SM 9), potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=99%, [M+H]+=380.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO.O>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1ccc(CCCCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc(CCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 22.5 %

Procedure:
To a mixture of 4-(4-phenylbutyl)phenyl acetate (8.29 g) in methanol (112 ml) and water (97 ml) was added sodium carbonate (13.10 g). The reaction was refluxed. After 3.5 hours, the reaction mixture was allowed to cool to room temperature. After 25 minutes at room temperature, the reaction mixture was treated with 5N HCl (50 ml). It was then concentrated in vacuo to remove the majority of the methanol present. Diethyl ether (250 ml) was added to the residue, then the material was treated with 1N HCl (3×100 ml) and the phases were separated. The material was dissolved in diethyl ether, then the denied compound was isolated by flash silica-gel filtration, eluting with hexane/ethyl acetate (20:1, 92×13 ml). The fractions containing the denied compound were combined and concentrated in vacuo to give 1.57 g of 4-(4-phenyl butyl)phenol an oil. Upon standing at room temperature the oil crystallized out.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].BrC1C=CC(OC)=C(N[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])C=1.CCCCCCC.C(OCC)(=O)C.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: COc1ccc(Br)cc1NC(=O)OC(C)(C)C
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC#N
Product: COc1cc(NC(=O)OC(C)(C)C)ccc1Br

Procedure:
The compound was prepared from 4-bromo-3-methoxyaniline in the manner described for compound (2): 1H NMR (DMSO-d6, 400 MHz) δ 9.46 (s, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 6.95 (d, 1H), 3.78 (s, 3H), 1.48 (s, 9H); TLC (heptane/ethyl acetate 8:2) Rf 0.37; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.60 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.O>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.C(#N)C>[CH:24]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][O:6][CH:7]3[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1cc(C2CC2)c2c(c1)C(C1=NCCN1)OCC2
Temperature: 120 °C

Procedure:
The mixture of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 11, 0.15 g), sodium carbonate (0.27 g), bis(triphenylphosphine)palladium(II) chloride (0.02 g), cyclopropylboronic acid (0.09 g), water (1 ml), and acetonitrile (2 ml) was heated in a microwave oven at 120° C. for 15 min. The title compound was purified with separation methods A and G. (Yield 8 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.C(O)C>O>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][C:1]#[N:2]
Reactant: COc1ccc(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)c(CC#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:28][CH:27]=[CH2:26])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 55 °C
Yield: 105.7 %

Procedure:
A solution of 1,3-di-N-butyl xanthine (10 g, 38 mmol) in anhydrous DMF (80 ml) was treated with K2CO3 (5.2 g, 38 mmol) followed by allyl bromide (3.6 ml, 42 mmol). The mixture was heated at 55° C. under nitrogen for 18 hours. After cooling to rt the mixture was partitioned between water and EtOAc. A few mls of 2M HCl (aq) was added to aid separation. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to afford the title compound as an off-white solid (12.23 g, 106%). m/z 305.3[MH+].
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:26])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([O:21][CH:22]([F:24])[F:23])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Cl>C(OCC)C>[CH:1]1([N:4]2[C:14]3[C:13](=[CH:18][C:17]([F:19])=[C:16]([F:20])[C:15]=3[O:21][CH:22]([F:24])[F:23])[C:12](=[O:26])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The whole of the ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate [(XIX), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (c) anove] was dissolved in 150 ml of anhydrous diethyl ether, and then 0.39 g (0.0098 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added in portions, whilst stirring at room temperature, to the resulting solution. After completion of the addition, the stirring was continued at room temperature for an additional 1 hour, and then the mixture was acidified by the addition of 1N aqueous hydrochloric acid with vigorous stirring. The reaction mixture was filtered and washed with water and with diethyl ether, in that order, to give 1.44 g of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless needles, melting at 224°-226° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C1COCC1>[S:1]1[C:5]([CH:21]([OH:22])[C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc3ccccc3s2)cc1

Procedure:
a-(2-benzo[b]thienyl)-4-methyoxybenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles. 1.0 g), t-BuLi (1.7 m, 10.4 mmoles, 6.1 ml), 4-methoxy-benzaldehyde (8.9 mmoles, 1.1 ml) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided 1.75 g (87%) of a yellow solid.