Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH3:27][NH:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:28]([CH2:29][CH:30]4[CH2:32][CH2:31]4)[CH3:27])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CNCC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, potassium iodide and 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran are treated with methyl(cyclopropylmethyl)amine to give 8-chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine. Preparation 31 8-Bromo-1-[[(cyclopropylemethyl)ethylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[C:17]([F:29])=[C:18]([CH:26]=[CH:27][CH:28]=1)[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[I-].[Na+].C(N(CC)CC)C>C(#N)C.O.C(OCC)(=O)C>[C:22]([NH:21][C:19]([C:18]1[C:17]([F:29])=[C:16]([CH:28]=[CH:27][CH:26]=1)[CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NC(=O)c1cccc(CBr)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Yield: 79.2 %

Procedure:
To a stirred mixture of tert-butyl piperazine-1-carboxylate (3.53 mmol, 658 mg) in acetonitrile (30 mL) was added 3-(bromomethyl)-N-tert-butyl-2-fluorobenzamide (3.21 mmol, 925 mg), sodium iodide (0.321 mmol, 48.1 mg) and triethylamine (4.82 mmol, 0.671 ml, 487 mg). The reaction mixture was stirred at reflux for 4 hours and then was diluted with water and ethyl acetate. The organic layer was separated, dried and concentrated under reduced pressure. Purification by silica chromatography (eluting with 5% methanol/dichloromethane) gave the title compound (1 g). MS (ESI) m/z 394.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[I:21]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([I:21])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Clc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,4-dichloropyridine (5.2 g, 35.137 mmol) and diisopropylamine (3.911 g, 38.651 mmol) in dry THF (40 ml) cooled at −78° C. under a nitrogen atmosphere, was added n-butyllithium (24.157 ml, 38.651 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at −78° C. for 45 min., then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 ml) was added dropwise and the mixture was further stirred at −78° C. for 1 h. The mixture was allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM up to 20% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D12 (7.8 g, 81%)
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:26]([CH3:27])[CH2:25][CH2:24][C:23]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38]([CH3:45])[CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:33][CH:32]=3)=[O:29])=[CH:22][C:21]=2[CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:27][N:26]1[C:20]2[CH:19]=[CH:18][C:17]([C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)=[CH:46][C:21]=2[CH:22]=[C:23]([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][N:38]([CH3:45])[CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:36]=2)=[O:29])[CH2:24][CH2:25]1
Reactant: [O-]B([O-])Oc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
In water/ethanol/toluene(1:1:10, 18.0 ml) were dissolved 4-trifluoromethoxyphenyl borate (208 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (407 mg), and to the mixture was added potassium carbonate (279 mg). Under argon atmosphere, the mixture was stirred for 30 minutes, and the mixture was added tetrakistriphenylphosphine palladium (39 mg). Under argon atmosphere, the mixture was refluxed for 16 hours, and the mixture was diluted with ethyl acetate (200 ml). The mixture was washed with water (50 ml) and saturated brine (50 ml), and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel. column chromatography (75 g, ethyl acetate→ethyl acetate/ethanol=20:1) and recrystallized from ethanol to give 1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-trifluoromethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 315) (148 mg, 31%).
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=O.Cl.[C:22]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[NH:24])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][NH:25][C:22]1[N:23]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:4]([C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][N:24]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCNC(=N)N
Reactant: CN(C)/C=C(/C(=O)c1ccc(C#N)cc1)c1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(C#N)cc2)n1
Temperature: 100 °C
Yield: 83 %

Procedure:
4-[(2E)-3-(dimethylamino)-2-imidazolylprop-2-enoyl]benzenecarbonitrile (6 M) in NMP (5 ml) was added to a stirred mixture of N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride (3 M) and Cs2CO3 (2.4) in NMP (15 ml). The reaction was heated to 100° C. for 48 hours. The reaction was followed by HPLC. Upon completion, the reaction was partitioned with water (50 ml) and dichloromethane (250 ml). The organic layer was separated and washed with water (2×50 ml), brine (50 ml), dried Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography eluting with 10% methanol in dichloromethane. After stripping off the solvents and drying in vacuo, (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)carboxamide was obtained as a dark red glass in 83% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH3:9].C=O.[C:13](=O)([O-])[O-:14].[Na+].[Na+].[OH-].[Na+]>Cl.C(O)(=O)C>[CH3:9][C:5]1[S:6][C:7]([CH2:13][OH:14])=[CH:8][C:4]=1[CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1sccc1CN(C)C
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(CO)cc1CN(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N,N,2-trimethyl-3-thiophenemethanamine (6.1 g), paraformaldehyde (3.0 g) in conc. hydrochloric acid (20 ml) and acetic acid (45 ml) was stirred at 0° to 5° C. for 1 hour, and at 8° for 72 hours. The mixture was added to an ice-cold, saturated solution of sodium carbonate. Aqueous 5M sodium hydroxide was added and the mixture was stirred for 20 hours. The solution was extracted with chloroform and the organic extract was washed with dilute sodium hydroxide and saturated brine, dried and evaporated to leave an oil. This residue was distilled to give the title compound (6 g) as a pale yellow oil b.p. 120°/0.1 mm. The oxalate salt was formed in ethanol and ethyl acetate m.p. 129°-131° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1>CC(C)=O>[CH3:9][C:8]1([CH3:13])[O:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)CO
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 6265.8 %

Procedure:
In a pear-shaped flask equipped with a calcium tube, a condenser, and a Dean-Stark trap, 100 g of glycerine, 300 ml of acetone, 3 g of p-toluenesulfonic acid monohydrate, and 300 ml of petroleum ether were placed, and heated to reflux in an oil bath set at 50° C.. After 12 hours, when about 23 ml of water was collected and no further formation of water was confirmed, the reaction mixture was cooled to room temperature. 3 g of sodium acetate was added, and the mixture was stirred for 30 minutes. Petroleum ether and acetone were distilled off in an evaporator. The resulting crude product was purified by vacuum distillation to give 130.6 g of 2,3-O-isopropylideneglycerol in the form of colorless, transparent liquid at 91% yield. 1H-NMR spectral data are shown below:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:22](=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13](=[CH2:22])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A mixture of methyl 3,5-bis(trifluoromethyl)benzeneacetate (Description 1, 10.0 g, 35 mmol), paraformaldehyde (5.2 g, 175 mmol), potassium carbonate (14.5 g, 105 mmol) and tetra-n-butyl ammonium iodide (650 mg, 1.75 mmol) in toluene (200 mL) was heated at 80° C. for 4 hours, cooled and stirred at room temperature for 16 hours. The mixture was filtered through a bed of Celite™, washing with ethyl acetate (2×100 mL). The combined filtrates were washed with water (100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (100:0 increasing to 90:10) to give the title compound as a clear oil (6.2 g, 60%). 1H NMR (400 MHz, CDCl3) δ 3.86 (3H, s), 6.05 (1H, s), 6.59 (1H, s), 7.86 (1H, s) and 7.88 (2H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([OH:22])=O)=[CH:17][C:16]=3[CH:23]=2)=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6]1(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4].[CH3:32][NH:33][CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([N:33]([CH3:34])[CH3:32])=[O:22])=[CH:17][C:16]=3[CH:23]=2)=[C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:6]1(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)O)cc3c2)=C(c2ccccc2)S1(=O)=O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)N(C)C)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 70 °C
Yield: 51 %

Procedure:
A mixture of 5-[(2-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-1-benzofuran-2-carboxylic acid (example 51) (0.100 g, 0.227 mmol), dimethylamine in THF (2M, 0.321 ml), EDC (0.132 g, 0.681 mmol), HOBt (0.065 g, 0.249 mmol) and TEA (0.090 ml, 0.681 mmol) in DMF (2 ml) was heated at 70° C. for 18 h. EtOAc was added and the mixture was washed with brine, evaporated and the residue was purified by flash chromatography (Horizons Biotage) using 50-65% EtOAc in hexane as eluent to give the title compound (0.054 g, 51%); 1H NMR (500 MHz CDCl3); δ 7.18 (dd, 1H), 7.14-7.10 (m, 3H), 7.08-7.02 (m, 2H), 6.99 (s, 1H), 6.91 (d, 1H), 6.84 (dd, 1H), 3.81 (t, 2H), 3.30 (bs, 3H), 3.14 (bs, 3H), 1.94-1.86 (m, 2H), 1.56-1.46 (m, 2H), 1.02 (t, 3H); 13C NMR (125 MHz CDCl3): δ 161.0, 159.5, 152.1, 151.0, 132.1, 131.4, 129.5, 129.5, 128.3, 127.1, 124.9, 121.6, 115.9, 111.9, 111.4, 111.2, 40.5, 30.5, 20.3, 13.8.; Mass Spectrum M+H+ 468.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[N:11][N:10]=2)[CH2:5][CH2:4]1.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)(=O)OC2C(F)=C(F)C(F)=C(F)C=2F)C=CC=CC=1.Cl.C(OCC)C>CN(C=O)C.C(Cl)Cl.CS(C)=O>[ClH:25].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[N:11][N:10]=3)[CH2:7][CH2:8]2)=[O:32])=[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=1
Reactant: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=P(Oc1c(F)c(F)c(F)c(F)c1F)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 140.9 %

Procedure:
Dissolve N-methyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-amine (100 mg, 0.31 mmol), 4-chloro-2-(methylsulfonyl)benzoic acid (87 mg, 0.37 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol) in DMF:DMSO=4:1 (2 mL) at 60° C. Cool to 0° C. and add pentafluorophenyl diphenylphosphinate (250 mg, 0.65 mmol) in DMF:DMSO=1:1 (1 mL) to the solution. Stir the mixture at 60° C. overnight. Cool the reaction mixture to ambient temperature and dilute with CH2Cl2, wash with brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the product. Add excess 1 N HCl in diethyl ether (1 mL, 10 mmol) to the isolated product and remove the solvent to provide the title compound (150 mg, 84%). ES/MS m/z 539.0 (M+1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:15]=1)[C:10]([OH:12])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:15]=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH:8]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1cc(OCC=C(C)C)cc(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)cc(OCC=C(C)C)c1
Yield: 39 %

Procedure:
In a manner identical to Example 15, 3,5-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 0.78 g (39%) of the aimed compound. 1H-NMR (CDC13)δ: 6.94(2H, d, J=2.4 Hz), 6.61(1H, t, J=2.4 Hz), 5.49(1H, t, J=5.4 Hz), 4.51(4H, d, J=6.8 Hz), 3.28-3.13(1H, m), 2.95-2.81(1H, m), 2.16-2.54(1H, m), 2.33-2.22(1H, m), 2.20-2.00(4H, m), 1.98-1.86(1H, m), 1.79(6H, s), 1.74(6H, s), 1.12(3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20](/[CH:21]=[CH:22]/[CH:23]=O)=[CH:19][CH:18]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][CH:23]=[C:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:25][CH:26]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1cccc(-c2nc(CCOc3ccc(/C=C/C=O)cc3)c(C)o2)c1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cccc(-c2nc(CCOc3ccc(C=CC=C4OC(=O)NC4=O)cc3)c(C)o2)c1
Yield: 34.3 %

Procedure:
A mixture of (E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde (1.20 g), 2,4-oxazolidinedione (0.525 g), piperidine (0.09 g) and ethanol (20 ml) was heated for 5 hours under reflux. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and, then, concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (50:1) was obtained 5-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamylidene]-2,4-oxazolidinedione (0.51 g, 34%). Recrystallization from dichloromethane-methanol gave pale yellow prisms, m.p.213-214° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[N:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)=[O:20])=[N:2]1.N1C2C(=CC=CC=2)C(/C=C/C2C=CC=CC=2NC(C2C(C(O)=O)=NC=CC=2)=O)=N1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:23](=[O:25])[C:22]3[C:21](=[N:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:20])=[N:2]1
Reactant: O=C(O)c1cccnc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1cccnc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cccnc2C(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 38 %

Procedure:
To a solution of (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}nicotinic acid or (E)-3-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}pyridine-2-carboxylic acid (20 mg, 0.052 mmol) obtained in Step 1 in THF (1.0 mL), 1-hydroxybenzotriazole monohydrate (1.6 mg, 0.010 mmol) and EDC (15 mg, 0.078 mmol) were added, followed by heating under reflux for 30 minutes. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10), crystallized from DMF/water (1/1) to obtain Compound 205 (7.2 mg, 38%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[C:7]=2[CH:15]=1.B(Br)(Br)Br.C(O)C>C(Cl)CCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH3:13])([CH3:14])[C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C(C)(C)OC(=O)N2
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCCl
Product: CC1(C)OC(=O)Nc2ccc(O)cc21
Reaction time: 8 h

Procedure:
An amount of 237.5 gm (1.146 mol) of 6-methoxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 2.4 liters of dry ethylene chloride, and 125 ml (330.3 gm=1.3 mol) of boron tribromide are added thereto dropwise, under stirring, at -30° to -40° C. After the addition is complete, the mixture is allowed to return to ambient temperature and left overnight. Then, 1 liter of 50% ethanol is added dropwise, under cooling and stirring, and the mixture is evaporated down to about 500 ml and then diluted with 3 liters of water. The precipitate is subjected to suction filtration and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:18]=1>CN(C)C(=O)C>[CH3:30][O:29][CH:26]([O:27][CH3:28])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxybenzonitrile (0.129 mol) in N,N-dimethyl-acetamide (200 mL) was stirred at room temperature and K2CO3 (0.147 mol) was added, then 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.086 mol) was added and the reaction mixture was stirred for 24 hours at 130° C. The solvent was evaporated and the residue was stirred in H2O. After extraction with CH2Cl2, the organic layer was separated, dried, filtered off and the solvent was evaporated. The residue was purified over a silica gel filter (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as residue.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11]N)[C:4]=2[O:3]1.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)C.O1CCOCC1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[NH:11][C:10]=3[C:4]=2[O:3]1
Reactant: O=C1CCNCC1
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: FC1(F)Oc2ccc3c4c([nH]c3c2O1)CCNC4
Temperature: 110 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
The (2,2-difluoro-benzo[1,3]dioxol-4-yl)-hydrazine (753 mg, 4.00 mmol) and 4-piperidone hydrochloride (543 mg, 4.00 mmol) in ethanol (10 mL) were heated to reflux for 45 min. The 4M HCl in dioxane (2 mL) was added and heating continued for 2 h. A sample was removed and after bubbling HCl gas briefly was heated in the microwave to 110° C. for 10 min. The rest of the material was processed in 5 batches and the combined black reactions filtered, washed with a little water and then precipitation with Et2O:Hexane 1:2 (c.f. 10 mL) before drying the resulting grey solid (147 mg, 13% yield)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:27])[CH2:10][CH2:9][C:8]2[C:11]([CH3:26])=[C:12]([O:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].[I-:28].[Na+].CC(C)=O.O>CCOCC>[CH3:1][O:2][C:3]([C:5]1([CH3:27])[CH2:10][CH2:9][C:8]2[C:11]([CH3:26])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][I:28])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(OCCCOS(C)(=O)=O)c(C)c(C)c2O1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)C1(C)CCc2c(C)c(OCCCI)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 75.9 %

Procedure:
A mixture of the crude methanesulfonate from Example 14 (about 0.932 mmole), 595 mg of sodium iodide, and 5 ml of acetone was stirred at room temperature for 43.5 hours then treated with water and worked-up with ether in the usual manner (the ether extracts were additionally washed with dilute sodium bisulfite solution). The oily product (390 mg) was chromatographed on 20 g of silica gel. Elution with 19:1 and 9:1 hexane-ethyl acetate afforded 306 mg (76.0%) of racemic-3,4-dihydro-2,5,7,8-tetramethyl-6-(3-iodopropoxy)-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless oil. In another experiment, iodide prepared in this way crystallized to a solid, mp 73°-75.5° C.