Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[CH:9][N:8]=1.[B:14](OCCCC)([O:20]CCCC)[O:15]CCCC.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:12]=[C:11]([B:14]([OH:20])[OH:15])[CH:10]=[CH:9][N:8]=1
Reactant: Fc1cc(I)ccn1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OB(O)c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of n-butyl lithium (3.2 mL 2.5M, 8.0 mmol) in dry diethyl ether (20 mL) at −78° C. was added a solution of 2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and the reaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate (2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 hours. Water (5 mL) was added followed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve the solids. The organic phase was separated. The aqueous phase was acidified to pH 3 using 6N hydrochloric acid and the resulting white solid was collected by filtration and dried under vacuum to give the title compound, 0.74 g (78%). 1H NMR (DMSO-d6) δ 8.65 (broad s, 2H), 8.21 (d, 1H), 7.59 (t, 1H), 7.37 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[N:5]1[C:12](Cl)=[N:11][C:9](Cl)=[N:8][C:6]=1Cl>O>[N:1]1([C:6]2[N:8]=[C:9]([N:1]3[CH2:4][CH2:3][CH2:2]3)[N:11]=[C:12]([N:1]3[CH2:4][CH2:3][CH2:2]3)[N:5]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Product: C1CN(c2nc(N3CCC3)nc(N3CCC3)n2)C1
Yield: 78 %

Procedure:
Compound LXXVI was prepared after the method of Schaefer (J Am Chem Soc (1955) 77 p592B). The hydrochloride salt of azetidine was reacted with cyanuric chloride in water to give compound LXXVI as a white solid (yield 78%) having a melting point of 225°-238° C. The 1Hnmr of this compound indicated that its identity was correct and that its purity was adequate for subsequent reactions without further purification.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][N:9]([CH2:32][CH2:33]Cl)[C:10]1[CH:30]=[C:29]([Cl:31])[C:13]2[O:14][C:15]3[C:24]([CH3:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][C:16]=3[S:17](=[O:20])(=[O:19])[CH2:18][C:12]=2[CH:11]=1>CO>[Cl:31][C:29]1[C:13]2[O:14][C:15]3[C:24]([CH3:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][C:16]=3[S:17](=[O:20])(=[O:19])[CH2:18][C:12]=2[CH:11]=[C:10]([N:9]2[CH2:8][CH2:7][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:33][CH2:32]2)[CH:30]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: NCC1CC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(CC4CC4)CC3)cc1CS2(=O)=O

Procedure:
Cyclopropylmethyl amine (0.30 mL, 3.34 mmol) was added to a solution of Example 102j (0.2 g, 0.42 mmol) in methanol (5 mL), followed by the addition of n-tetrabutylammonium iodide (0.01 g, 0.020 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 10 h. The reaction mixture was brought to room temperature, concentrated, treated with water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified by crystallisation (ethylacetate-pet-ether). Yield: 0.114 g, (53.7%). 1H NMR (DMSO-d6): δ 0.1 (d, 2H, CH2), 0.50 (d, 2H, CH2), 0.90 (m, 1H, CH), 2.30 (d, 2H, CH2), 2.70 (s, 3H, CH3), 3.20-3.25 (m, 4H, 2CH2), 5.15 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.15 (s, 1H, Ar), 8.0 (s, 1H, Ar), 8.20 (s, 1H, Ar).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:18])[F:17])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:37])[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:17])[F:18])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]5[N:38]=[N:39][NH:40][N:34]=5)=[CH:31][C:30]=4[F:37])[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Fc1cc(-c2nn[nH]n2)ccc1N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)F)noc1C1CC1)C2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (70 mg, 0.14 mmol) was dissolved in N,N-dimethylacetamide (2 ml), sodium azide (91 mg, 10 eq, 1.40 mmol) and ammonium chloride (75 mg, 10 eq, 1.40 mmol) were added, and the mixture was stirred at 120° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2×20 mL). The combined organics were separated, dried (MgSO4), and evaporated in vacuo. The product was purified by mass directed reverse phase HPLC to give a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>O1CCCC1.C(#N)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:37])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Yield: 70.9 %

Procedure:
The (3-hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (1.67 g, 7.49 mmol) and triphenylphosphine (2.61 g, 9.96 mmol) were combined and dissolved in tetrahydrofuran (40 mL). Carbon tetrabromide (3.23 g, 9.74 mmol) was dissolved in acetonitrile (20 mL) and added dropwise to the reaction while stirring. After stirring for 5 h, the reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded (3-bromomethyl-phenyl)-carbamic acid tert-butyl ester (1.52 g, 78%) as a white powder: H1-NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 4.46 (2H, s), 6.47 (1H, bs), 7.06 (1H, d, J=7.2 Hz), 7.19-7.27 (2H, m), 7.51 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:14]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:14])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1Br
Temperature: 45 °C
Yield: 48.2 %

Procedure:
A suspension of 2-amino-5-chloropyridine (5.14 g, 40 mmol) and anhydrous sodium acetate (3.29 g, 40 mmol) in acetic acid (25 mL) was mechanically stirred and warmed to a bath temperature of 45° C. A solution of bromine (2.1 mL, 40 mmol) in acetic acid (2 mL) was added over 1 hour. The resulting orange mixture was cooled to 15° C. and filtered. The solids were taken up in 400 mL of water, the suspension made basic by addition of 1 N NaOH and the suspension extracted with ethyl acetate (5×100 mL). The combined extracts were washed with 10% NaHSO3 (1×100 mL) and were dried over MgSO4. Concentration afforded 2-amino-3-bromo-5-chloropyridine (4 g, 48), mp 82-84° C.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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.O>[Cl:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: O=c1c(Br)coc2ccccc12
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2cccc(Cl)c2)coc2ccccc12
Yield: 50.1 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 3-chlorophenylboronic acid (256 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 38 (193 mg, 50%) as a white solid. Analytical data for isoflavone 38: 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 7.73 (app t, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.59-7.45 (m, 3H), 7.39 (d, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.1, 156.4, 153.6, 134.6, 134.1, 133.9, 130.0, 129.2, 128.6, 127.4, 126.7, 125.7, 124.7, 124.5, 118.4; LCMS: Mass calculated for C15H9ClO2, [M+H]+, 257. Found 257.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([N:15]2[CH2:22][CH2:21][C@:20]3([CH3:26])[C:23]([CH3:25])([CH3:24])[C@H:16]2[CH2:17][C:18]2[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][C:19]=23)=[O:14])[CH2:9][CH2:8]1)=[O:6].Cl.C(OCC)(=O)C>CO>[OH:31][C:30]1[C:18]2[CH2:17][C@@H:16]3[C:23]([CH3:25])([CH3:24])[C@:20]([CH3:26])([C:19]=2[CH:27]=[CH:28][CH:29]=1)[CH2:21][CH2:22][N:15]3[C:13]([C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 M aqueous NaOH solution (3.5 mL) is added to a solution of cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid methyl ester (1.2 g) in methanol (20 mL). The resulting solution is stirred at room temperature overnight. Then, 4 M hydrochloric acid is added, the resulting mixture is extratced with ethyl acetate, and the combined extratcs are dried (Na2SO4). After removal of the solvent, the residue is triturated with a mixture of acetonitrile and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(Cc2ccc(F)cc2)C3)cc1
Yield: 97.6 %

Procedure:
A solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 677.7 mg, 0.50 mmol), 4-fluorobenzaldehyde (0.13 mL, 0.60 mmol), acetic acid (0.03 mL, 0.60 mmol), and NaBH(OAc)3 (148.4 mg, 0.70 mmol) in methylene chloride (15 mL) was stirred at rt for 24 h. Sodium hydroxide (1N) was added, and the solution was extracted with diethyl ether (3×30 mL). The combined ether layers were dried (sodium sulfate), filtered, and evaporated. The residue was purified by silica gel column, eluting with 3:1 hexanes:ethyl acetate. The product was isolated as a white solid (218.1 mg, 97%). LC-MS m/z (MH+) 447, retention time 2.65 min (method 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[N:35]1([CH2:41][CH2:42][CH2:43][NH2:44])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][CH2:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: NCCCN1CCOCC1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCCN3CCOCC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (80 mg, 0.15 mmol) and 3-(4-morpholinyl)-1-propanamine (0.10 mL, approx. 6.9 mmol) the title compound was obtained as a white solid (85 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=5.1 Hz, 1H), 7.52-7.67 (m, 1H), 7.36 (dd, J=7.6, 1.6 Hz, 1H), 7.21-7.32 (m, 2H), 7.07-7.21 (m, 3H), 6.14 (br. s., 1H), 3.57 (br. s., 4H), 3.20-3.36 (m, 8H), 2.36-2.41 (m, 1H), 1.65 (br. s., 2H), 1.31 (d, J=6.8 Hz, 6H). MS (ESI): 633.5 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.40 g), 8N aqueous sodium hydroxide solution (0.40 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.35 g, yield 91%) as colorless crystals. melting point>240° C. (decomposition).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[N+:1]1([O-:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2ncccc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ccccc21
Reaction time: 24 h
Yield: 90 %

Procedure:
To a 100 mL round bottom flask containing a solution of quinoline (12.2 mmol) in 50 mL of DCM was added 5.3 g of m-CPBA (30.6 mmol). The reaction mixture was stirred for 24 h. The reaction mixture was then diluted DCM (100 mL), washed with 5% NaOH (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give solid quinoline-N-oxide (90-95% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[OH2:14]>C(O)(=O)C>[O:14]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: O
Solvent: CC(=O)O
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 60 °C
Yield: 79.6 %

Procedure:
In a 100 ml three-necked round bottomed flask is placed 1.0 g. of N-(4,5,6,7-tetrahydrobenz[b] thien-4-yl) acetamide, 5 ml each of H2O and glacial acetic acid, and 5.13 g. of solid cobaltic acetate (assay 23.56% Co(III) by weight) prepared by method of Example V). The mixture is stirred and heated to 60° C. for 11 hours under a nitrogen atmosphere. Treatment as in Example V yields 1.04 g. of material containing 79.6% of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1C=O.[CH:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])OCC>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1[CH:13]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22]
Reactant: O=Cc1oc2ccccc2c1Br
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(OCC)c1oc2ccccc2c1Br
Reaction time: 8 h

Procedure:
To a solution of 2.6 g of 3-bromo-2-benzo[b]furancarboxaldehyde (see M. Cugnon de Sevricourt and M. Robba, Bull. Chim. Soc. Fr., 1977, 142) in 2.7 ml of triethyl orthoformate was added 33 mg of paraoluene sulfonic acid and the solution stirred at at roon temperature overnight. The solution was diluted with a 5% sodium carbonate solution and extracted with ether. The ether extracts were dried over sodium sulfate and evaporated to give 3-bromo-2-(diethoxymethyl)-benzo[b]furan as a liquid; 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>C(O)C>[CH2:1]([O:8][N:9]=[C:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=NOCc2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(C(=NOCc2ccccc2)c2cccc(N)c2)cc1
Yield: 100 %

Procedure:
A mixture of isomer A of 4-methoxyphenyl 3-nitrophenyl ketone O-benzyloxime (974 mg) [prepared as described in step (a) above] and tin (II) chloride (2.55 g) in ethanol (30 ml) was heated under reflux for 1 hour. After removal of the ethanol by evaporation, the residue was diluted with ethyl acetate. The ethyl acetate was washed with a 5N aqueous solution of sodium hydroxide, with water and then with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and evaporated under reduced pressure, to afford isomer A of the title compound (893 mg) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:21][OH:22])[CH:18]([CH3:20])[CH3:19].[CH3:23][C:24](=[CH2:26])[CH3:25].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:24]([O:16][C:15](=[O:17])[CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[C:2](=[O:1])[C:3]([CH:18]([CH3:20])[CH3:19])([CH2:21][O:22][C:3]([CH3:18])([CH3:4])[CH3:2])[CH2:4]2)([CH3:25])([CH3:23])[CH3:26]
Reactant: CC(C)C1(CO)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C1(COC(C)(C)C)Cc2cc(OCC(=O)OC(C)(C)C)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
A solution of (1-oxo-2-hydroxymethyl-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (4.0 g., 0.012 mole), isobutylene (6 ml.), chloroform (20 ml.) and concentrated sulfuric acid (0.1 ml.) is sealed from the atmosphere and stirred at 25° C. for two weeks. After this time, the reaction mixture is poured into saturated aqueous sodium bicarbonate. The chloroform layer is separated, washed with water, dried and the chloroform distilled at reduced pressure affording tert.-butyl-(1-oxo-2-isopropyl-2-tert.-butoxymethyl-6,7-dichloro-5-indanyloxy)acetate which is hydrolyzed in a refluxing solution of methanolic potassium hydroxide. Acidification of the hydrolysis solution affords (1-oxo-2-isopropyl-2-tert.-butoxymethyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 148°-149° C. after recrystallization from acetic acid-water.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([O:17]C)=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:20].CO>ClCCl>[BrH:20].[NH2:2][C:3]1[C:4]([OH:17])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(N)cccc1-c1csc(C(=O)O)c1
Reactant: BrB(Br)Br
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: Nc1cccc(-c2csc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The reaction mixture was reacted at room temperature for 4.5 hours. The reaction mixture was added with 5 mL of methanol and concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19c (80 mg, yield 17.5%) as a grey solid.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=5[F:19])[C:4]=4[CH:3]=3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Fc1cc(F)c(CN2CCNc3ncc(I)cc32)cc1F
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)c(F)cc3F)CCN4)cc2)CC1
Yield: 30 %

Procedure:
7-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (30% yield). M.p. (foam), LCMS: m/z=482.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.35-2.52 (m, 4H), 3.39-3.42 (m, 2H), 3.42-3.56 (m, 2H), 3.58-3.66 (m, 2H), 3.68-3.88 (m, 2H), 4.45 (s, 2H), 4.98 (s, 1H), 6.72 (s, 1H), 6.89-7.02 (m, 1H), 7.08-7.15 (m, 1H), 7.35-7.44 (m, 4H), 7.70 (s, 1H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]1[C:21]2[CH2:20][CH:19]([CH2:22][NH2:23])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH:1]([NH:23][CH2:22][CH:19]1[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:21]=2[CH2:20]1)=[O:3]
Reactant: O=CO
Reactant: NCC1Cc2ccccc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCC1Cc2ccccc2Cc2ccccc21
Reaction time: 1 h

Procedure:
A mixture of formic acid and acetic anhydride (1:1, 20 ml) is prepared at 0° to 10° C and added to 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine (15.0 g). The mixture is stirred for 1 hr. and then allowed to stand for 18 hr. Water (100 ml) and ice chips are are added. After stirring for 15 min., the mixture is rendered alkaline with dilute NaOH solution and extracted with ether. The extract is washed with water, dried (MgSO4) and concentrated to afford N-formyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10-methylamine, m.p. 109° - 111° C, δmaxCHCl3 3445, 3350, 1685 cm-1, after recrystallization from ether.