Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[C@@H:32]([OH:33])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O[C@@H](c1ccccc1)[C@H]1COCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3[C@@H](O)c3ccccc3)sc21
Temperature: 90 °C
Yield: 68.7 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 134 mg) and (S)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 9, 111 mg) in DMF (3 mL) is treated with diisopropylethylamine (0.5 mL). The mixture is heated at 90° C. overnight. After cooling to room temperature, the solution is poured into ethyl acetate (75 mL) and washed with dilute pH 4 phosphate buffer (10 mL), dilute pH 7 phosphate buffer (10 mL), and brine (10 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (methanol/CH2Cl2, 1-3%) and ethyl acetate-hexanes crystallization to afford 0.13 g of the title compound Physical characteristics. M.p. 129-134° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.60, 8.67, 7.41-7.25, 5.33, 5.07, 4.54, 4.17, 3.88, 3.81, 3.73, 3.6, 3.5-3.4, 2.94, 2.6, 2.4-2.3; HRMS m/z 538.1561 (M+H)+. Anal. Found: C, 62.33; H, 5.25; N, 7.75.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[NH:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22]2[N:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
1-chloroethyl chloroformate (2.9 g, 20 mmol) was added dropwise to a stirring mixture of 6-(1-benzyl-piperidin-4-yl)-pyridazin-3-carbonitrile (D2) (1.5 g, 5.1 mmol) and diisopropylethylamine (2.6 g, 20 mmol) in dichloromethane (50 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then the solvent evaporated in vacuo. Methanol (50 ml) was added to the residue and the mixture was refluxed for 2 h. The solvent was evaporated in vacuo and the residue purified by column chromatography (silica gel; 5-12% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and the solvent evaporated in vacuo to yield D3 (0.9 g, 90%) as a solid. C10H13N5 requires 203. Found 204 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:25]C(=O)C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:5]2=[O:24]>Cl.CO.C(Cl)Cl>[NH2:25][C:3]1[C:2]([NH2:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:24])[C:6]([OH:23])([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[O:21][CH3:22])[C:7]2=[O:11]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(NC(C)=O)c2C1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2ccc(N)c(N)c2C1=O
Yield: 46.4 %

Procedure:
N-(5-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (85 mg, 0.19 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 40 min at 80. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (30 mg, 44%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) were dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (52.6 g, 0.38 mol) was added thereto, and the mixture was stirred for 20 h at 100° C. After completion of the reaction, water was added. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([CH2:9][N:10]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[CH2:15][CH2:14][N:13]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[CH2:12][C:11]1=[O:34])(O)=[O:7].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:32][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:13]2[CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:10]([CH2:9][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:11](=[O:34])[CH2:12]2)=[O:33])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)O)C(=O)C2)c1
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)N3CCCC3)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Pyrrolidine (117 μl, 1.41 mmol) was added to a solution of 1-carboxymethyl-4-(3-methylphenyl)carbamyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonin(373 mg, 0.94 mmol), EDC (181 mg, 0.94 mmol) and HOBt (127 mg, 0.94 mmol) in DMF (3 ml) at room temperature. The reaction mixture was stirred at room temperature for 28 hours, diluted with water (50 ml), and extracted with ethyl acetate (50 ml). The organic extract was washed with 10% citric acid solution (50 ml), brine (2×50 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate as eluant. (138 mg, 34%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:37]3[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][CH:38]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: C[C@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccnn2COCC[Si](C)(C)C)C1

Procedure:
(S)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 13.2, 60 mg, 0.130 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (85 mg, 0.261 mmol), Pd(PPh3)2Cl2 (10.98 mg, 0.016 mmol), Na2CO3 (55.3 mg, 0.521 mmol), DME (553 μL), water (158 μL) and EtOH (79 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.3 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc, from 10% to 60% EtOAc) to yield the title compound as a colorless oil. UPLC-MS (Condition 3) tR=1.26 min, m/z=578.3 [M+H]+, m/z=622.3 [M+formic acid-H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=O)[CH3:29])[C:5]2=3)[CH:14]=1.CO>C1COCC1>[CH2:28]([NH:27][CH2:26][CH2:25][O:24][C:6]1[C:5]2[C:4]3[C:12]4=[C:13]([O:15][CH2:16][CH:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:11]4[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:14]=[C:2]([CH3:1])[CH:3]=3)[CH3:29]
Reactant: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Solvent: CO
Solvent: C1CCOC1
Product: CCNCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 72.3 %

Procedure:
To a mixture of N-{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide (0.212 g, 0.53 mmol) in THF (10 mL) is added borane-methylsulfide complex (0.15 mL, 1.6 mmol). The mixture is refluxed at 85° C. for 16 hours. After cooling, methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added then removed. The residue is dissolved in CH2Cl2/CH3OH (1:5, 15 mL). Conc. HCl is added and the mixture is heated at 65° C. for 1 h. The mixture is removed from heat, neutralized with aqueous potassium carbonate and then partitioned between water and CH2Cl2 The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2Cl2 (5:95) as eluent gave 0.148 g (70%) of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (TLC: MeOH/CH2Cl2, 5/95, Rf=0.38); conversion to the maleic acid salt and recrystallizing from absolute ethanol gave 0.0223 g of N-ethyl-2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine, maleic acid salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[CH:13][CH:12]=3)=[O:16])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A suspension of 3′-methyl-[1,1′-biphenyl]-4-carboxylic acid of Step B (0.50 g, 2.36 mmol) in thionyl chloride (3 mL) was heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow oil. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to a solution of the 10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine (0.65 g, 3.53 mmol) and N,N-diisopropylethyl amine (0.90 mL, 5.17 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white foam. Purification of the residue by flash chromatography using a solvent gradient from 15% to 25% of ethyl acetate in hexane gave a white foam which was crystallized by sonication from ethyl acetate/hexane to provide the title compound (0.74 g, 82.8%) as a white solid, m.p. 128-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:30])=[C:17]([C@:19]2([CH3:29])[C:25]([F:27])([F:26])[CH2:24][O:23][CH2:22][C:21](=[O:28])[NH:20]2)[CH:18]=1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[CH2:8][CH2:7][CH:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:30])=[C:17]([C@:19]4([CH3:29])[C:25]([F:26])([F:27])[CH2:24][O:23][CH2:22][C:21](=[O:28])[NH:20]4)[CH:18]=3)[C:5]2=[N:4][CH:3]=1
Reactant: C[C@]1(c2cc(N)ccc2F)NC(=O)COCC1(F)F
Reactant: O=C1CCc2cc(Cl)cnc21
Agent: O=C([O-])O
Agent: [B][B][B][B][B][B][B][B][B][B]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=O)COCC1(F)F
Temperature: 23 °C
Reaction time: 22 h
Yield: 87.2 %

Procedure:
To a solution of 3-chloro-5,6-dihydro-[1]pyrindin-7-one (28 mg, 167 μmol) in methanol (6 ml) and dichloromethane (750 μl) at 23° C. was added (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (intermediate A21A) (49.9 mg, 182 μmol) followed by decaborane (5.6 mg, 167 μmol) and the mixture was stirred at 23° C. for 22 hours. After completion, the mixture was poured into aqueous NaHCO3 solution, extracted with ethyl acetate, the organic layers were dried over Na2SO4 and the solvent evaporated. The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the (5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (62 mg, 87%) as an orange solid. MS (ISP): m/z=426.1 [(M+H)+] and 428.1 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])=[C:4]([CH3:18])[CH:3]=1.C(N1C=CN=C1)(N1[CH:25]=[CH:24]N=C1)=O.C(O)C>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[CH2:11][C:12]([O:14][CH2:24][CH3:25])=[O:13])=[C:4]([CH3:18])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)C(C)(C)CC(=O)O)c(C)cc1Br
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C(=O)c1cc(C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.2 g (10 mmol) of 4-(4-bromo-2,5-dimethyl-phenyl)-3,3-dimethyl4-oxo-butanoic acid in tetrahydrofuran is combined with 3.60 g (11 mmol) of carbonyldiimidazole and stirred for 1 hour at ambient temperature. The solvent is replaced by 20 ml of ethanol and the mixture is heated to boiling for 2 hours. Then the solvent is distilled off, the crude product is taken up in methylene chloride, washed with water, dried with sodium sulphate, concentrated and purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=3:97).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:7][C:8]=1[CH:14]=[O:15]
Reactant: COc1ccc(CC(F)(F)F)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(F)(F)F)cc1C=O
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a stirred solution of Compound 45 (760 mg, 4.00 mmol) in dry CH2Cl2 (15 ml) was added TiCl4 (1.67 g, 8.80 mmol) via a syringe with ice-cooling. After 15 min, to this was added a solution of dichloromethyl methyl ether (920 mg, 8.00 mmol) in dry CH2Cl2 (5 ml) at same temperature. The reaction mixture was stirred at 0 C. for 15 min, and then for 1.5 h at room temperature. The mixture was diluted with water (20 ml) with ice-cooling and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated in vacuo to give crude product as a yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (40:1-20:1) to give Compound 46 (500 mg, 57%) as a colorless solid(needle).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].C(NCC)C>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:16][CH2:13][C:14]#[C:15][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C#CCO)cc1
Reaction time: 1 h
Yield: 34.8 %

Procedure:
2.5 g of tetrakis(triphenylphosphine)palladium (0) was added to 50 ml of a solution of 10 g of ethyl p-bromobenzoate in benzene at room temperture. The obtained mixture was stirred at that temperature for one hour, followed by the addition thereto of 2.5 g of propargyl alcohol, 0.84 g of cuprous iodide and 19 g of diethylamine. The obtained mixture was stirred at room temperature for 26 hours and filtered through Celite. Water (50 ml) was added to the filtrate and the obtained mixture was extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of hydrochloric acid and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 20% ethyl acetate/n-hexane) to give 3.1 g of the title compound as a pale-yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.[Br:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)cc1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(Br)cc4)cc3)cc2)cc1
Temperature: 95 °C
Yield: 69.9 %

Procedure:
A mixture of compound 8 (3.0 g, 6.3 mmol), 1-bromo-4-iodobenzene (3.57 g, 12.6 mmol), Pd(PPh3)4 and potassium carbonate (1.74 g, 12.6 mmol) in dioxane/water (40 ml/8 ml) was degassed and heated at 95° C. for 24 hours. After being cooled to RT, yellow solid precipitated and collected by filtration. The solid was recrystallized in dichloromethane/methanol to give a pale yellow solid (2.22 g). The filtrate was loaded on silica gel and purified by flash column to give additional amount of yellow solid 9 (0.42 g). Total amount is 2.64 g, in 83% yield.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].C(O[CH2:24][CH3:25])(=O)C>CN(C=O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:18]=[CH:25][C:24]3/[C:14](=[CH:1]/[C:3]#[N:4])/[C:15]4[CH:18]=[CH:6][CH:5]=[CH:10][C:16]=4[CH2:12][CH2:8][C:9]=3[CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reaction time: 0.17 h
Yield: 63 %

Procedure:
2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.85 g, 4.8 mmol) was dissolved in DMF (15 mL), and the solution was added with potassium tert-butoxide (0.60 g, 5.3 mmol) at 0° C. followed by stirring for 10 min. Thereto was added a solution of the residue obtained above in DMF (8 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the mixture, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-1/3) to give (E)-[2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (1.28 g, 63%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>C(#N)C>[Br-:25].[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH:7]([N+:14]2[CH:18]=[CH:17][N:16]([CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])[CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Solvent: CC#N
Product: O=C(Cn1cc[n+](C(c2ccccc2)c2ccc(-c3ccccc3)cc2)c1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.4 %

Procedure:
15.1 g (0.05 mol) of 1-[α-(4-biphenylyl)-benzyl]-imidazole and 10 g (0.05 mol) of ω-bromoacetophenone are suspended in 500 ml of acetonitrile. After stirring for 15 hours at room temperature, the resulting clear solution is concentrated to about 50 ml. The crystals which hereupon separate out are filtered off and dried. 21 g (82.5% of theory) of 1-[α-(4-biphenylyl)-benzyl]-3-phenacylimidazolium bromide of melting point 210° C. (with decomposition) are obtained.
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[I:12][CH2:13][C:14]#[C:15]O.Cl.C(=O)(O)[O-:19].[Na+]>C1(C)C=CC=CC=1.CCOCC.C(N(CC)CC)C>[I:12][CH:13]([O:4][C:3](=[O:19])[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[Cl:1])[C:14]#[CH:15]
Reactant: OC#CCI
Reactant: O=C([O-])O
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CC(I)OC(=O)C(Cl)c1ccccc1

Procedure:
24.6 g of alpha-chlorophenylacetic acid chloride, dissolved in 20 ml of toluene, were added dropwise to a mixture of 23.7 g of 3-iodopropynol, 15 g of triethylamine and 100 ml of toluene. The reaction temperature was 60° C. The reaction mixture was finally taken up in 100 ml of ether and the ethereal solution was subsequently extracted first with 1N hydrochloric acid and then with saturated sodium bicarbonate solution. Finally, the organic phase was dried with sodium sulfate. After distilling off the ether, 36.5 g, corresponding to 84% of the theoretical yield, of alpha-chlorophenylacetic acid iodopropargyl ester were obtained.