Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:24][C:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]=4[N:15]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:25])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:24][C:17]4[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:16]=4[N:15]=3)=[CH:12][C:8]([C:9]([N:39]3[CH2:42][CH:41]([C:43]4[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=4)[CH2:40]3)=[O:10])=[C:7]([CH3:25])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CCN(C)CC3)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CCN(C)CC3)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoic acid (compound 82.9, 40 mg, 0.12 mmol), EDC.HCl (45.4 mg, 0.24 mmol, 2.00 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 23 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL). The resulting solution was stirred for 4 h at room temperature then quenched by the addition of water/ice (10 mL). The resulting mixture was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the crude product which was purified by Prep-HPLC using the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, WATER WITH 0.03% NH4OH and CH3CN (30% CH3CN up to 43% in 8 min, up to 100% in 4 min, down to 30% in 2 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing clean product were combined to yield 2.2 mg (4%) of the title compound as a white solid. m/z (ES+) 480 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of EXAMPLE 324J (1.00 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.90 g) in tetrahydrofuran (15 mL) was added diisopropylethylamine (4.75 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and the solid washed with dichloromethane. The reaction mixture was combined with the washings were concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[NH2:8])[CH:2]=[CH2:3].[CH2:14]1[CH:19]2[C:20]([O:22][C:23](=O)[CH:18]2[CH2:17][CH:16]=[CH:15]1)=[O:21].C(O)(=O)C>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]2[C:20](=[O:21])[C:19]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[C:23]2=[O:22])[C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[CH:2]=[CH2:3]
Reactant: O=C1OC(=O)C2CC=CCC12
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: C=CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 19A, 6.8 g of THPA and 100 mL of glacial acetic acid was heated at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature, poured into 450 mL of water and extracted with ether. The extract phase was washed with water, dried (Na2SO4), and filtered, and the solvent was evaporated from the filtrate. The residue was flash-chromatographed on silica gel, with a 15:85 v:v mixture of ethyl acetate and hexane as eluent, to give N-(3-(allyloxy)-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide (19B), as an orange oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCNCc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
[[2′-[(t-Butylamino)sulfonyl]-1,1′-biphenyl-4-yl]methyl] bromide (0.94 g), n-heptylamine (0.28 g) and potassium carbonate (0.35 g) were added to dimethylformamide and the mixture was stirred at room temperature. Sixteen hours and 30 minutes later, ethyl acetate (30 mL) was added, and the resulting mixture was washed three times with brine (100 mL, each). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (chloroform/ethyl acetate) to afford N-[[2′-[(t-butylamino)sulfonyl]-1,1′-biphenyl-4-yl]methyl]-N-heptylamine as a yellow oil (0.43 g). Yield: 42%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22]>CN(C=O)C.[Cu]>[O:7]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1cnccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cnccc1Oc1ccccc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of phenol (1.34 g, 14.3 mmol) in DMF (25 ml) was stirred with anhydrous potassium carbonate (0.99 g, 7.2 mmol) at 70°-80° C. for 40 minutes. 4-Chloro-3-pyridinecarboxaldehyde (2.02 g, 14.3 mmol) and copper bronze powder (0.10 g) were added and the resulting suspension stirred at 100°-110° C. for 2 hours. The reaction mixture was cooled, filtered and the residues washed with ether. The combined ether washings were diluted to 400 ml with more ether, washed with saturated brine (4×) and the solvent removed to give 4-phenoxy-3-pyridinecarboxaldehyde as a pale yellow crystalline solid (2.62 g); melting point 74°-75° C.; infrared max (nujol) 1590, 1695, 2760 cm-1 ; 1H NMR delta (CDCl3) 6.75 (1H broad), 7.15 (2H,d), 7.35 (1H,t), 7.50 (2H,t), 8.5-9.7 (2H,broad), 10.7 (1H,s).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]1[CH:2]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=O)=[C:11]([F:19])[C:10]=1[F:20].[C:21]([C:23]1[C:24](=[C:31]([C:34]#[N:35])[C:32]#[N:33])[O:25][C:26]([CH3:30])([CH3:29])[C:27]=1[CH3:28])#[N:22]>C(O)(=O)C.N1C=CC=CC=1>[CH:5]12[CH2:8][CH:1]([CH2:7][CH2:6]1)[CH:2]1[CH:4]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=[CH:28][C:27]2[C:26]([CH3:29])([CH3:30])[O:25][C:24](=[C:31]([C:32]#[N:33])[C:34]#[N:35])[C:23]=2[C:21]#[N:22])=[C:11]([F:19])[C:10]=1[F:20]
Reactant: O=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 100-mL round bottom flask with stirbar was added 4-(3-aza-tricyclo[3.2.1.02,4]oct-3-yl)-2,3,5,6-tetrafluoro-benzaldehyde (0.35 g, 1.23 mmol), 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile (0.39 g, 2 mmol), pyridine (5 mL) and acetic acid (several drops). The mixture was stirred under nitrogen at room temperature for 3 days. TLC showed that one red fluorescent product had formed as the main product. The reaction was stopped. The product mixture was poured into ice-water (500 mL) and vigorously stirred for 4 h. The crude products were extracted with CH2Cl2 (100 mL×5). The combined organic layer was dried over anhydrous MgSO4. After removing solvent, the crude organic product was adsorbed on silica gel, placed at the top of a silica column and eluted (hexane/EtOAc=2/1). Fraction containing only the first red fluorescent product were combined and concentrated to give a red solid, which was recrystallized from 1-propanol to give the final product as red needles. Mp 233° C. IR (neat): 2951, 2228, 1573, 1481, 1390, 1366, 1163, 1107, 983, 962 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=16.8 Hz, 1H), 7.23 (d, J=16.8 Hz, 1H), 2.70 (br s, 4H), 1.80 (s, 6H), 1.63-1.51 (m, 3H), 1.34-1.27 (m, 2H), 0.98-0.92 (m, 1H); 13C NMR (100 MHz, CDCl3): 176.4, 173.4, 148-139 (m), 132.5, 118.8 (t), 111.4, 110.6, 109.9, 97.6, 95.3 (m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[C:3]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2C)n(C)n1
Yield: 81.5 %

Procedure:
Using N-[6-(3-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.402 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (83 mg, 0.523 mmol), triethylamine (122 mg, 1.21 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (146 mg, 82%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].Br[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[O:13][CH2:15][C:16]#[N:17])([O-:3])=[O:2]
Reactant: N#CCBr
Reactant: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: N#CCOc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
3,5-Dinitrophenol (15.0 g) and 10.75 g of bromoacetonitrile were dissolved in 85 ml of 2-butanone and the solution was treated with 33.78 g of potassium carbonate. The heterogenous mixture was stirred and heated at 70° C. for 5 hours, cooled to room temperature, poured into ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane/hexane (3:1) to give 11.24 g of (3,5-dinitrophenoxy)-acetonitrile as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:47]=[CH:46][C:38]([CH2:39][NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])=[CH:37][CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Br)cc1)C1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCc1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (93.8 mg, 0.21 mmol), cyclopropanecarboxylic acid 4-bromo-benzylamide (50.6 mg, 0.20 mmol), and Pd[P(Ph)3]4 (13.7 mg, 5.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 15.0 mg. MS: 498.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.61-0.79 (m, 4H), 1.56-1.69 (m, 3H), 2.11-2.35 (m, 1H), 3.38-3.59 (m, 2H), 4.25-4.43 (m, 3H), 4.89-5.15 (m, 2H), 7.00-7.65 (m, 12H), 7.85-7.95 (m, 1H), 8.51-8.63 (m, 1H), 10.07-10.16 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CCC(CC(=O)OC)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC(=O)OC)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of 3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-pentanoic acid methyl ester (50 mg, 0.18 mmol) (prepared according to example 2, steps 1-2) in DMF (10 mL) are added 3-bromomethyl-4,6-dimethyl-1,2-benzisothiazole (70 mg, 0.271 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature under a nitrogen atmosphere. The solution is heated at 100° C. for 2 hours. The solution is cooled down and water is added. The solution is extracted with EtOAc and the combined organic layer is dried with MgSO4. The solution is filtered and the filtrate is concentrated. The residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford 3-[1-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (65 mg, 80%) as a colorless foam.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C@:11]([NH2:18])(CBr)[C:12](OC)=O)([O:6][C:7](C)(C)C)=[O:5]>C1COCC1>[NH2:18][C@@H:11]([CH2:12][N:2]([CH3:3])[CH3:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC
Reactant: COC(=O)[C@@](N)(CBr)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2M solution of dimethylamine in THF (2.5 mL) is added dropwise to a stirred solution of methyl (S) 2-BOC-amino-3-bromo-propionate (0.45 g; 1.42 mmol) (Weiss R. G. et al., J. Org. Chem, 36, 403, 1971; Kang M. et al., ibidem, 61, 5528, 1996) in anhydrous THF (10 mL) at 25° C. The mixture is stirred overnight at r.t. and evaporated to dryness in vacuum. The residue is partitioned between Et2O (30 mL) and aqueous 0.5 N NaOH (2×5 mL); the ethereal extracts are combined, washed with brine, dried over Na2SO4 and evaporated to dryness to obtain 0.34 g (1.22 mmol) of methyl (S)-2-amino-3-dimethylamino-propionate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCCC1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-cyclohexyl-1,3-dihydro-indol-2-one (0.11 g, 0.44 mmol) (from Example 19b supra), 3-chlorobenzyl bromide (0.11 g, 0.53 mmol) (Aldrich), potassium iodide (87 mg, 0.53 mmol) and potassium carbonate (0.13 g, 0.95 mmol) in acetone (3 mL) was heated at 60° C. for 2 days in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 5:95, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-cyclohexyl-1,3-dihydro-indol-2-one as a white solid. (Yield 30 mg, 18%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[O:7]=[P:8](Cl)([Cl:10])[Cl:9]>>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][P:8]([Cl:10])([Cl:9])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NCCCBr
Agent: Br
Product: O=P(Cl)(Cl)NCCCBr

Procedure:
To a three-necked flask fitted with a thermometer, distillation column and a nitrogen tube was added 3-bromopropylamine hydrobromide (12 g, 0.055 mol) and 20 mL of POCl3 (0.22 mol). The reaction mixture was heated to reflux under nitrogen overnight. Excess POCl3 was removed at the pump at room temperature (attempted distillation resulted in decomposition). The crude dichloridate, 15.4 g, was used directly in the procedure of the following Example V.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.O>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
In a 30 ml-round-bottomed flask, 2.00 g (10.6 mM) of 6-hydroxy-2-naphthoic acid, 4.0 ml of acetic anhydride and two drops of concentrated sulfuric acid were placed, followed by heat-stirring for 1 hour at about 90° C. The reaction mixture was cooled to room temperature and poured into 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and recrystallization from ethanol to obtain 1.48 g of 6-acetoxy-2-naphthoic acid (Yield: 60.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2ccnc2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 25 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (2.0 g), 60% sodium hydride in oil (0.50 g, degreased with hexane), imidazole (0.50 g) and dimethylformamide (25 ml), the title compound (0.57 g) was obtained as a tan amorphous solid, MS, m/z: 389 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([Br:17])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:17][C:10]1[CH:11]=[CH:12][C:13]2[C:8]([CH:9]=1)=[N:7][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[C:14]=2[O:15][CH3:16]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2ccc(Br)cc2nn1CC(C)(N)C#N
Product: COc1c2ccc(Br)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (50 mg, described in Example 129) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (80 mg, 96%). MS (ES): M/Z [M+H]=513. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.89 (d, 1H), 6.97 (dd, J=9.1, 1.5 Hz, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.86-7.91 (m, 2H), 7.94-7.99 (m, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN1CCN(C)C1=O.[OH-].[Na+]>C(O)(C)C>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: CC(C)O
Product: Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 340 g of p-phenylphenol, 630 g of p-chlorotoluene, 68 g of 1,3-dimethyl-2-imidazolidinone and 81.0 g of sodium hydroxide was stirred at 160° to 168° C., and the water was separated azeotropically was removed by means of a trap. After adding 5.0 g of 8-hydroxyquinoline-copper complex, the mixture was further stirred at 155° to 165° C. for 15 hours. GLC analysis showed that the conversion of p-phenylphenol to the desired product was 98%. The same after treatment as in Example 1 gave 490 g of a crude product in 94% yield. It was dissolved in isopropyl alcohol, decolorized with active carbon and clay, and recrystallized to give 4-biphenylyl p-tolyl ether as white crystals melting at 97° to 98° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)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>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]4[C:19]([F:18])=[C:24]([CH:23]=[CH:22][CH:21]=4)[CH:25]=[O:26])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: O=Cc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Temperature: 70 °C
Yield: 56.8 %

Procedure:
500 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, 473 mg of 2-fluoro-3-formylbenzeneboronic acid and 93 mg of tetrakis(triphenylphosphine)palladium are placed under a stream of argon in a round-bottomed flask comprising a mixture, degassed beforehand under a stream of argon, of 5 ml of acetonitrile, 5 ml of toluene and 6 ml of a 2M sodium carbonate solution. The reaction mixture is heated at 70° C. for 21 h. After cooling, the reaction mixture is diluted with ethyl acetate and water and then the organic phase is separated, dried and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/ethyl acetate 98/02 mixture. 324 mg of compound are obtained.