Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:15][C:14]1[C:6]([Cl:5])=[C:7]2[C:11]([CH2:20][CH2:21][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Thionyl chloride (5.73 mL, ˜79 mmol) and 2,3-dichloro-benzoic acid (commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene was heated to reflux until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to AlCl3 (7.0 g, ˜53 mmol) in dichloroethane at 10-20° C. Ethylene was bubbled through the mixture for 4 h. The mixture was stirred overnight and quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated. The concentrate was added to a slurry of AlCl3 (9.0 g) and NaCl (2.4 g) at 130° C. The resulting mixture was stirred at 180° C. for 2 hours after which it was cooled to room temperature and quenched with ice followed by concentrated HCl. The mixture was extracted with CH2Cl2 (3×500 mL) and the combined organic extracts were concentrated and purified by column chromatography using 20% EtOAc:hexane eluant to give 6.8 g (80%) of 6,7-dichloro-1-indanone. Use of 6,7-dichloro-indan-1-one in Method NINETEEN produced 4-(4,5-dichloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 153).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]=[O:20])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1.[F:21][C:22]([SiH3])([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>CCOCC.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]([OH:20])[C:22]([F:24])([F:23])[F:21])=[C:6]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=Cc1ccc(F)cc1NC(=O)CCc1ccccc1
Reactant: FC(F)(F)[SiH3]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1C(O)C(F)(F)F
Temperature: 23 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a mixture of aldehyde from Step 3 (252 mg, 0.929 mmol) and THF (8 mL) under argon at 0° C., was added trifluoromethylsilane (132 mg, 0.929 mmol), followed by tetrabutylammonium fluoride (1M solution in THF, 50 mL). The reaction was warmed to 23° C. After 2 h at 23° C., the reaction was treated with 3N HCl (125 mL). After 4 h, the reaction was diluted with ether (75 mL), washed with brine (2×100 mL), and dried (MgSO4). Concentration in vacuo afforded a brown oil (214 mg, 67.4%) which was taken on to the next step without further purification: 1H NMR (CDCl3) δ2.63 (t, J=7 Hz), 2.97 (t, J=7 Hz), 4.68 (br s), 4.88 (q, J=6 Hz), 6.73-6.82 (m), 7.11-7.35 (m), 7.83-7.92 (m), 8.85 (br s). IR (neat) 3450-3050, 1667 cm−1. MS (EI) 341 (M+), 323, 209, 140. Anal. Calc'd. for C17H15NO2F4: C, 59.82; H, 4.43; N, 4.10. Found: C, 59.81; H, 4.57; N, 4.08.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH2:16](Br)[CH:17]=[CH2:18]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][N:6]([CH2:18][CH:17]=[CH2:16])[CH3:7])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CNC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(C)CC(=O)OCC
Yield: 88.5 %

Procedure:
Into a 100 ml four-necked flask there were placed 11.7 g of sarcosine ethyl ester, 15 g of triethylamine and 50 ml of benzene, and 12.1 g of allyl bromide was gradually added dropwise thereto at room temperature with thorough stirring. The reaction solution was then heated and refluxed for 3 hours. After cooling, the deposited triethylamine hydrobromide was removed by filtration and the benzene removed under reduced pressure. The residue obtained was distilled under reduced pressure to obtain 13.9 g of the objective N-allylsarcosine ethyl ester (b.p.110 116° - 118° C, nD27.0 1.4308).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>>[O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acid with oxalyl chloride.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(Cl)cc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 4-chlorobenzylamine (71 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.3 mg, 80% yield). 1HNMR (500 MHz, CDCl3) δ: 12.25 (1H, s), 7.80 (1H, br s), 7.52–7.46 (1H, m), 7.81 (2H, d, J=8.55 Hz), 7.25 (2H, d, J=8.24 Hz), 7.05 (2H, dd, J=8.54, 7.32 Hz), 4.55 (2H, d, J=6.10 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H15ClF2N3O3 (M+H): 406.0770; found: 406.0775.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][C:32]=3[O:40][CH:41]([CH3:43])[CH3:42])=[N:20]2)=[CH:15][CH:14]=1.[NH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[N:22]([C:1]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][C:32]=3[O:40][CH:41]([CH3:42])[CH3:43])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CCOc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Reactant: O=C(Cl)Cl
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.7 %

Procedure:
Phosgene (0.325 mL, 0.64 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (0.126 mL, 0.896 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (60 mg, 0.128 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and evaporated. The residue was kept under high vacuum for 30 min. Methylene chloride (5 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0.22 mg, 2.56 mmol) in methylene chloride (5 mL) at 0° C. over 15 min. After 1 h, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Purification using reverse phase HPLC gave [4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (6.5 mg, 8%). HR-MS (ES, m/z) calculated for C31H35N4O3Cl2[(M+H)+]581.2081, observed 581.2086.
Reaction SMILES: [OH:1]C1C=CC=CC=1C(O)=O.C(OO)(C)(C)C.[CH3:17][CH:18]([C:20](=[CH:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:21]#[N:22])[CH3:19]>C(Cl)Cl.[Se](=O)=O>[OH:1][C:24](=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:23]=[C:20]([CH:18]([CH3:17])[CH3:19])[C:21]#[N:22]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Agent: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=C(O)C=C(C#N)C(C)C
Reaction time: 0.5 h
Yield: 317.6 %

Procedure:
To a suspension of selenium dioxide (58 mg) and 2-hydroxybenzoic acid (365 mg) in methylene chloride (10.5 ml) was gradually added an aqueous solution of 80% t-butyl hydroperoxide (11.6 ml) with stirring on a water bath. After 30 minutes, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.56 g, 26.8 mmol) was added to the mixture, which was then allowed to stand at room temperature for 30 hours. Most of the solvent was removed by evaporation in vacuo, and the residue was dissolved in ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated. The resultant residue was subjected to silica gel column chromatography to give the aimed 4-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (2.53 g, 31%). The starting material was also recovered (3.10 g, 40%) in the column chromatography. The yield of the aimed product based on the consumed starting material was 52%.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.CCOC(C)=O>[C:17]([NH:25][C:26](=[O:27])[NH:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)OC(C)(C)C)sc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate (example 64b) (16 g, 67.14 mmol) in dioxane (200 mL), was added benzoyl isocyanate (10 g, 67.14 mmol). The reaction mixture was stirred at rt overnight, and upon completion was diluted with EtOAc, washed with NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to yield tert-butyl 5-(3-benzoylureido)-4-cyano-3-methylthiophene-2-carboxylate (21.78 g, 84%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ1.54 (s, 9H), 3.58 (s, 3H), 7.58 (t, J=7.5 Hz, 2H), 7.71 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.5 Hz, 2H), 12.25 (br s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:21][C:22]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:21][C:22]3[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=3)[N:4]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: CCOC(=O)Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(C(=O)OC)on3)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A mixture of ethyl [4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl]acetate (2.00 g), methyl 3-hydroxyisoxazole-5-carboxylate (0.974 g), anhydrous potassium carbonate (0.941 g) and N,N-dimethylformamide (40 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through silica gel. The filtrate was concentrated to give methyl 3-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)isoxazole-5-carboxylate as colorless crystals (2.02 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-126° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[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:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)O1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.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>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 51.1, 50 mg, 0.115 mmol) Pd(Ph3P)4 (13 mg, 0.011 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (36 mg, 0.172 mmol) and toluene (0.5 mL) was stirred for 15 min. at RT. K3PO4 (73 mg, 0.345 mmol) was added and the RM was stirred at 110° C. for 6 h. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative SFC (Column DEAP, from 7% to 12% in 6 min) to afford the title compound was lyophilized to afford an off-white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=435.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[N:5]([C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:6].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)[N:5]([CH3:6])[C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:8]
Reactant: COCCC1(C(=O)N(C)[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCC1(C(=O)N(C)[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a mixture of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-N-methyl-4-nitro-L-phenylalanine methyl ester (1.35 mmol, 530 mg), zinc dust (˜325 mesh, 13.5 mmol, 0.88 g, 10 equiv.) and ammonium chloride (20.2 mmol, 1.08 g, 15 equiv.) was added methanol (10 mL) and water (5 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 2 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material, the reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The mixture was concentrated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded 490 mg (100%) of a yellow oil. HR MS (C20H30N2O4): Obs. mass,362.2202. Calcd. mass, 362.2206 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=O)[S:5][C:6]=1Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[C:20](=[O:23])([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:3]1[CH:2]=[C:6]([CH:20]=[O:23])[S:5][C:4]=1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:10]
Reactant: OB(O)c1ccccc1F
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2ccccc2F)c(-c2ccccc2F)s1
Temperature: 80 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
A suspension of 4,5-dibromothiophene-2-carbaldehyde (2.0 g), (2-fluorophenyl)boronic acid (1.6 g), tetrakis(triphenylphosphine)palladium (0) (855 mg) and sodium carbonate (2.0 g) in 1,2-dimethoxyethane (32 mL) and water (8 mL) was stirred at 80° C. for 6 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→9:1→17:3) to give the title compound as a colorless amorphous (yield 310 mg, yield 14%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: C1CCNC1
Product: O=C(c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1)N1CCCC1
Yield: 57 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and pyrrolidine following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1): tR=2.27 min; Mass spectrum (ESI+): m/z=429 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:12][C:13]1[C:23]2[O:22][CH2:21][CH2:20][CH2:19][O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.[C:24]([O-:27])([O-])=O.[K+].[K+]>>[O:22]1[CH2:21][CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:12][N:10]([CH2:12][C:13]3[C:23]4[O:22][CH2:21][CH2:20][CH2:19][O:27][C:24]=4[CH:16]=[CH:15][CH:14]=3)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[C:23]1=2
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1cccc2c1OCCCO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(CN(Cc2cccc3c2OCCCO3)c2ccc3[nH]cnc3c2)c2c(c1)OCCCO2

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 6-(bromomethyl)-3,4-dihydro-1,5-benzodioxepin (535 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.098 g (21.4%); MS m/z: 458.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.10 (quin, 4H, 3J=5.5 Hz); 4.10 (t, 4H, 3J=5.5 Hz); 4.15 (t, 4H, 3J=5.5 Hz); 4.61 (s, 4H); 6.58-6.60 (m, 2H); 6.76-6.85 (m, 6H); 7.31 (d, 1H, 3J=9.8 Hz); 7.88 (s, 1H); 11.89 (br s, 1H); HPLC (METHOD [A]): rt 16.11 min (92.3%)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](OC=O)(=[O:41])C>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH:39]=[O:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC(=O)OC=O
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(C=O)CCC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To 3.0 g (6.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 586) dissolved in 25 ml of ethyl acetate and cooled to 0° C., was added 2.4 g (30 mmole) of pyridine and 4.0 g (28 mmole) of formic acetic anhydride mixture (Example 621a). After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 2.5 g of the desired compound, mp 161°-163° C.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([Br:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]=[O:2])=[CH:10][CH:9]=1
Reactant: BrCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of dichloromethyl methyl ether (62 ml) in methylene chloride (40 ml) was added titanium tetrachloride (75 ml) over 10 minutes under a nitrogen atmosphere at 4-5° C. Then, a solution of phenethyl bromide (85 ml) in methylene chloride (50 ml) was added thereto over 50 minutes at 5-7° C. and the mixture was stirred for 5 hours while gradually raising the temperature of the mixture to room temperature. Water (200 ml) was added to the reaction mixture over 1 hour and the mixture was extracted with chloroform (200 ml). The chloroform layer was washed with water, a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (167 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=20:1) to give 4-(2-bromoethyl)benzaldehyde (32.3 g) as a yellow solid, melting point 50-52° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[C:6]([F:23])[CH:5]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([F:23])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-Ethoxy-2-fluoro-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (12 mmol) in CH2Cl2 (150 ml), TFA (29 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. The solvent is removed by evaporation and dried to give crude product, 1-(4-ethoxy-2-fluoro-phenyl)-piperazine. To the crude product in DMF (50 ml), potassium carbonate (30 mmol) is successively added at 0° C. The mixture is stirred at 0° C. for 15 min. 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7.H.-pyrrolo[2,3-.d.]pyrimidine-2-carbonitrile (12 mmol) is added to the mixture at 0° C. The reaction mixture is stirred at room temperature for 3 h and quenched with saturated ammonium chloride. The mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=2:1 (v/v).