Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)o1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromofuran-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 2.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. Then the mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V/V=1:1). The residue was dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)furan-2-carboxylic acid 9a (4.23 g, yield 56.1%) as a grey solid.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][S:23]([CH:20]4[CH2:22][CH2:21]4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)C1CC1
Yield: 2.5 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and cyclopropylsulfonyl chloride (119 mg, 0.85 mmol) according to the procedure described for example 27. Obtained the title compound as a white solid (7 mg, 2.5%), MS (ISP) m/e=364.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][NH2:32]>C(O)(C)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:32][CH2:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][N:25]4[CH3:24])[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Reactant: CN1CCCC1CCN
Solvent: CC(C)O
Product: CN1CCCC1CCNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Temperature: 85 °C
Yield: 17 %

Procedure:
To a stirred solution of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (50 mg, 0.154 mmol) in 1 mL of isopropanol was added excess of 2-(1-methylpyrrolidin-2-yl)ethanamine (1 mL). The mixture was heated to reflux at 85° C. overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give N-[2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-yl]-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]amine as peach solid in 17% yield (28.3% yield based on recovered starting material). 1H NMR (CDCl3): δ 8.58 (dd, 2H, J=1.4, 4.6 Hz), 7.59–7.62 (m, 2H), 7.25–7.32 (m, 3H), 7.04–7.14 (m, 3H), 6.83 (t, 1H, J=5.3 Hz), 5.98 (d, 1H, J=7.4 Hz), 3.40–3.55 (m, 2H), 3.13–3.19 (m, 1H), 2.43 (s, 3H), 2.36–2.43 (m, 1H), 2.20–2.29 (m, 1H), 1.66–2.20 (m, 6H); MS (ES+ve): 418 (10, M+3), 417 (20, M+2), 416 (60, M+1), 112 (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16](I)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=1)#[CH:22]>CN(C=O)C.[Cu](I)I.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>[C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=3)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(CO)cc3)c(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
A 2 mL Biotage™ microwave vial was charged with copper iodide (1.1 mg, 10 mol %), and Pd(PPh3)2Cl2 (2.1 mg, 5 mol %). A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 25.0 mg, 0.059 mmol) in DMF (0.5 mL) was added to the vial, followed by a solution of (4-ethynyl-phenyl)-methanol (15.0 mg, 0.118 mmol) in DMF (250 uL) and TEA (57 uL, 0.41 mmol). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 120° C. for 5 min. The solvent was removed in vacuo to give dark brown oil which was used in the next step without further purification. LR-MS (API-ES): calculated for C22H21ClN2O3S 428.1, observed m/e 429.0 (M+H)+ (Rt 3.05 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1.C(O)C.[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C=C/c1c(F)cc(OC)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.5 %

Procedure:
Ethyl (2E)-3-(2,6-difluoro-4-methoxyphenyl)acrylate (1.1 g, 4.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and ethanol (30 mL), 10% palladium-carbon (50% water-containing product, 0.30 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off and the obtained filtrate was concentrated to give the title compound (1.17 g, yield 100%) as a colorless oil. MS: m/z 245 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([O:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH3:28].FC(F)(F)C([O-])=O>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][C:35]2([NH:38][CH2:21][CH:20]([C:12]3[C:13]4[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=4[C:9]([OH:8])=[CH:10][CH:11]=3)[OH:24])[CH2:37][CH2:36]2)=[CH:39][CH:40]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: CCCCOc1ccc(CC2(N)CC2)cc1
Agent: O=C([O-])C(F)(F)F
Product: CCCCOc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 219 mg (1 mmol) 1-(4-butoxy-benzyl)-cyclopropylamine. Yield: 107 mg (20%, trifluoroacetate); mass spectroscopy: [M+H]+=427.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([NH:42][C:43](=[O:62])[NH:44][C@@H:45]([CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:28])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:38]([O:37][C:35](=[O:36])[C@@H:34]([NH:42][C:43](=[O:62])[NH:44][C@@H:45]([CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN1CCNCC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (S)-di-tert-butyl 2-(3-((S)-6-(11-(4-((benzyloxy)carbonyl)piperazin-1-yl)undecanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (1.50 g, 1.72 mmol) and ammonium formate (1.0 g) in ethanol (60 mL) was added palladium on carbon (300 mg). The reaction mixture was stirred at room temperature for overnight and filtered through a pad of celite followed by washing of the celite pad using ethyl acetate (EtOAc). The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (DCM). The DCM solution was washed using saturated sodium bicarbonate and then partitioned to separate the organic layer from the aqueous layer. Concentration of the organic layer under reduced pressure afforded the titled product as a yellowish solid (1.2345 g, 97% yield). MS (ESI), 740.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([S:14]C(=O)N(C)C)[CH:5]=1.CO[Na].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([SH:14])[CH:5]=1
Reactant: COC(=O)c1cc(OC)c(OC)c(SC(=O)N(C)C)c1
Agent: CO[Na]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(S)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a stirred solution 3-dimethylcarbamoylthio-4,5-dimethoxybenzoic acid methyl ester (800 mg, 2.67 mmol) in THF (21 mL) was added MeONa (0.5 M in MeOH, 21 mL) at room temperature and the reaction was heated to reflux. After refluxing for 3 h, the reaction mixture was cooled to room temperature, poured into 1 N HCl aqueous solution (150 mL) and extracted with mixture of EtOAc:hexane (1:1, 150 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give 3-mercapto-4,5-dimethoxybenzoic acid methyl ester (0.581 g).
Reaction SMILES: [CH3:1][C:2]([NH:10][CH3:11])([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([N:10]([C:2]([CH3:1])([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)(C)NC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)N(C)Cc1ccccc1

Procedure:
A mixture containing ethyl 3-methyl-3-methylaminobutanoate (95 g--see Preparation δ), benzyl bromide (72 ml), anhydrous potassium carbonate (138 g) and acetonitrile (500 ml) was heated under reflux for 1.5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (500 ml) and 10% aqueous potassium carbonate (300 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a mobile, colourless oil, yield 150 g.
Reaction SMILES: C(OC(=O)[CH2:5][C:6](=[O:21])[CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.N12CCN(CC1)CC2>Cl>[C:15]1([CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:6](=[O:21])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)CC(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Product: CC(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of β-oxo-δ-phenyl-benzene pentanoic acid ethyl ester (8.0 g, 0.026 mol) in 47.5 mL xylenes (15.0 eq), 1,4-diazabicyclo[2.2.2]octane (30.28 g, 0.269 mol, 10 eq) was added and the reaction mixture was first heated to reflux for 5 hours and then stirred at room temperature for 16 hours (D. H. Miles, et al, J. Org. Chem. 39, 2647 (1974)). The reaction mixture was then acidified (pH 1) with approximately 10 mL 5% HCl. This heterogeneous mixture was then filtered through Celite, thoroughly washing the bed of Celite with ether. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo to give a crude oil. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 4.0 g (0.018 mol, 70%) of the desired product.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]1[C:9]2=[CH:10][N:11]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:12]([C:13]3[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=3)=[C:8]2[C:7](=[O:28])[N:6]([CH3:29])[C:5]1=[O:30].O>C1COCC1>[CH3:3][N:4]1[C:9]2=[CH:10][N:11]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:12]([C:13]3[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=3)=[C:8]2[C:7](=[O:28])[N:6]([CH3:29])[C:5]1=[O:30]
Reactant: CCOC(=O)CCCn1cc2c(c1-c1cccc(C)c1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Lithium hydroxide (2.64 g, 63.0 mmol) was added to a solution of ethyl 4-(1,3-dimethyl-2,4-dioxo-5-m-tolyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoate (step 1) (4.83 g, 12.6 mmol) in THF (48 mL)/water (12 mL). The mixture was stirred at room temperature for 24 hours. The organic solvent was largely removed under vacuum, the residue was acidified to pH 1, using 1M. The precipitate was extracted into chloroform (1×100 mL, 4×50 mL). The combined organic extracts were dried with magnesium sulfate and the solvent was removed under vacuum. The resulting solid was dried under vacuum at 50° C. to give the title compound.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:33]2[NH:34][C:35](=[O:42])[C:36]([CH:39]([CH3:41])[CH3:40])([CH3:38])[N:37]=2)[N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([S:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:25][C:26]=1[C:33]1[NH:34][C:35](=[O:42])[C:36]([CH:39]([CH3:40])[CH3:41])([CH3:38])[N:37]=1
Reactant: CC(C)C1(C)N=C(c2nc(SCc3ccccc3)ccc2C(=O)O)NC1=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(SCc2ccccc2)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.0 g (0.005 mol) dicyclohexylcarbodiimide and 2.0 g (0.005 mol) 6-benzylthio-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinic acid are dissolved in 30 ml methylene chloride, then stirred for 4 hours at room temperature and allowed to stand overnight. The reaction mixture is filtered and the filtrate is then compressed. The oily residue crystallizes after a while.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: CNc1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccccc1Br
Temperature: 25 °C
Yield: 24 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.05 g, 0.2 mmol) and 2-bromo-N-methylaniline (0.044 g, 0.24 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 0.66 mL) was added and the reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction mixture was concentrated in vacuo, taken into DMF at 100 mg/ml and purified by preparative RP-HPLC to give 162bp. Yield=24% of theoretical. MS: (ESI+)=419.5
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([C:37](=[O:39])[CH3:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(C)=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL) was added acetic anhydride (0.5 mL). The solution was stirred at room temperature for 90 minutes when it was quenched by addition of 2 drops of water. The solution was dried in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 28 mg of the product (81%) as a clear gel. The NMR data of this compound shows two rotamers in a ratio of 70:30. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J=7 Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H), 3.40-3.52 (m, 2H), 3.46 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s, 3H), 4.07 (pent, 4H, J=7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22-5.30 (m, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.9 ppm; MS (m/z) 584.1 [M+H]+, 606.2 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[I-].[Na+]>>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)CCI
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCOc1cccc(C=O)c1
Yield: 92.6 %

Procedure:
The compound was synthesized as in Example 24.1, using 3-hydroxybenzaldehyde (200 mg, 1.64 mmol) in place of 4-hydroxybenzaldehyde and 1-iodo-3-methylbutane (649 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 3-(isopentyloxy)benzaldehyde (292 mg, quant. crude) as a dark yellow oil that was used without further purification or characterization.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][N:16]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:14])[CH:20]=2)[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc(C)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1

Procedure:
The title compound, was prepared from 4-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (example 1, step 4) and 2-Chloropyridine-4-boronic acid in accordance with the general method of example 1, step 6 to yield the final compound as a light yellow oil, MS (ISP): m/e=277.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][P:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH:17]=2)[NH:12][N:11]=1>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][P:20]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=P(Oc1ccc2[nH]nc(C3Cc4ccccc4N3)c2c1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Product: O=P(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)(c1ccccc1)c1ccccc1
Yield: 13.6 %

Procedure:
170 mg of diphenylphosphinic acid 3-(2,3-dihydro-1H-indol-2-yl)-1H-indazol-5-yl ester are stirred for 10 hours at 100° C. in dimethyl sulfoxide. The solvent is evaporated off under reduced pressure at 30° C. The reaction crude is purified by flash chromatography on silica (8 g Interchim cartridge), eluent: cyclohexane/ethyl acetate 4:6, 2:8; and ethyl acetate/methanol 9:1 to obtain 23 mg of diphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH2:8]([N:15]1[C:27]2[C:26]([S:28]([CH3:30])=O)=[C:25]([CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH:24]=[C:23]([CH3:38])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([N:15]1[C:27]2[C:26]([S:28][CH2:30][CH2:2][CH3:3])=[C:25]([CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH:24]=[C:23]([CH3:38])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(CC(=O)OC(C)C)c(S(C)=O)c2c1c1ccccc1n2Cc1ccccc1
Solvent: ClCCl
Product: CCCSc1c(CC(=O)OC(C)C)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Reaction time: 0.5 h

Procedure:
0.1 ml of anhydrous trifluoroacetic acid was added to 5 ml of a solution of 100 mg isopropyl (9-benzyl-4-methyl-1-methylsulfinylcarbazol-2-yl)acetate, as obtained in Example 215, in methylene chloride, and the reaction mixture was refluxed for 30 minutes. The solvent was then removed by evaporation under reduced pressure and the residue was dissolved in 2 ml of methylene chloride. 0.5 ml of n-propyl iodide, 1 ml of triethylamine and 1 ml of methanol were then all added to the resulting solution at room temperature and the reaction mixture was stirred for 30 minutes. After this time, the reaction mixture was diluted with an excess of ethyl acetate, and washed with a dilute aqueous solution of hydrogen chloride, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 4-6% v/v solution of ethyl acetate in hexane) to yield 86 mg of the title compound as a solid.
Reaction SMILES: [BH4-].[Na+].[NH:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13](OC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OS(O)(=O)=O>CO>[NH:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][OH:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(Nc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Nc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Under cooling with ice water, 7.2 g of sodium borohydride was gradually dropped into 4.5 g of methyl 3-anilinobenzoate dissolved in 20 ml of methanol. Then, the temperature was gradually raised and the reflux was carried out for 8 hours. The reaction mixture was poured into 10% H2SO4 aqueous solution which was being cooled with ice. 5.0 g of oily substance was obtained after the extraction with ether. In order to remove the remaining unreacted methyl ester, the hydrolysis was carried out with the addition of 5% KOH. The by-produced 3-anilinobenzoic acid was removed through alkali-washing to yield 3.5 g of 3-anilinobenzylalcohol.