Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([C:5]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH:9]([OH:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[C:19](=[O:21])[CH3:20])(=[O:4])[CH3:3].[C:28](OCC)(=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>O.C(Cl)(Cl)Cl.C(O)C>[C:19]([C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH:9]([OH:22])[CH2:8][O:7][C:6]1[C:5]2[C:2](=[O:4])[CH:3]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(O)c1C(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(C)=O)cccc2o1

Procedure:
A solution of 69.0 parts of sodium in 1000 parts of ethanol was added to a mixture of 360.3 parts of 1,3-bis-(2-acetyl-3-hydroxyphenoxy)propan-2-ol, 146.1 parts of diethyl oxalate and 250 parts of ethanol. The reaction mixture was refluxed for five hours, then poured into a stirred mixture of 700 parts of chloroform, 3,000 parts of water and 285 parts of concentrated hydrochloric acid. The solid obtained was removed by filtration, the chloroform phase of the filtrate separated and the aqueous phase extracted with chloroform. The combined chloroform extracts were washed with water and concentrated to give a solid which was removed by filtration. Evaporation of the chloroform from the filtrate gave a residue which, after fractional crystallization from ethanol, gave 36.0 parts of slightly impure ethyl 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 145°-148°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21]Br>C(#N)C>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrCCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCBr)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate D45 (5 g) and K2CO3 (12.48 g, 90 mmol) in Acetonitrile (150 mL) stirred under nitrogen was added 1,2-dibromoethane (33.9 g, 181 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was filtered, concentrated to give the crude as clear oil. The crude was purified to give the expected product D46 in 4.2 g, eluting with Petroleum oil/EtOAc=3/1. LCMS Retention time=1.76 mins, [M+H]+273 (5 min run)
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[N:23]=[N:22]1.C(N(CC)CC)C>CN(C=O)C>[C:7]([N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[N:23]=[N:22]1)([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:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(CCCCc2c[nH]nn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Reaction time: 8 h

Procedure:
A solution of 706 mg (5.06 mmol) triphenylchloromethane in 5.0 ml DMF was added at 0° C. to a solution of 500 mg (2.30 mmol) 4-(4-1H-[1,2,3]triazol-4-yl-butyl)-phenol and 512 mg (5.06 mmol) triethylamine in 5.0 ml DMF. The mixture was allowed to reach r.t. overnight and solvents were removed in vacuo. After distribution of the residue between water and ethyl acetate, the organic phase was dried (sodium sulphate), solvents distilled off and the residue purified by column chromatography on silica gel (heptane/ethyl acetate 2:1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([NH:17][C:18]([C:20]3[N:24]4[CH:25]=[CH:26][C:27](Br)=[CH:28][C:23]4=[N:22][CH:21]=3)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)[C:57]([O:59]CC)=[CH2:58])CCC.C(N(CC)CC)C.Cl>CO.C(Cl)Cl.CN(C=O)C>[C:57]([C:27]1[CH:26]=[CH:25][N:24]2[C:20]([C:18]([NH:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[N:9][N:8]4[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:19])=[CH:21][N:22]=[C:23]2[CH:28]=1)(=[O:59])[CH3:58]
Reactant: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(Br)ccn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
A dried flask flushed with nitrogen was charged with N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide (150 mg, 0.34 mmol), tri-o-tolylphosphine (20 mg, 0.067 mmol), tris-dibenzylideneacetone dipalladium (0) (31 mg, 0.033 mmol), anhydrous DMF (4.5 mL) and tributyl(1-ethoxyvinyl)stannane (0.13 mL, 0.39 mmol). The resulting mixture was immediately degassed under a nitrogen atmosphere, triethylamine (0.056 mL, 0.40 mmol) was added, and the flask was heated at 100° C. for 6 hours. To the cooled reaction was added concentrated aqueous hydrochloric acid (0.5 mL) and stirring was continued at ambient temperature for two hours. The reaction was quenched with excess saturated aqueous sodium bicarbonate, and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 4% MeOH/DCM as eluent to afford 55 mg of desired product as an off-white solid. MS (ES+APCI) m/z=410 (M+H) detected.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[CH:4][N:3]=1.[NH:31]1[C:39]2[C:34](=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH:31]1[C:39]2[C:34](=[C:35]([C:2]3[CH:7]=[C:6]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[CH:4][N:3]=3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1ccnc(Cl)c1)P(=O)(OC(C)C)OC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(C)OP(=O)(OC(C)C)C(F)(Cc1ccnc(-c2cccc3[nH]ncc23)c1)P(=O)(OC(C)C)OC(C)C
Yield: 30.7 %

Procedure:
Tetraisopropyl (2-(2-chloropyridin-4-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (78 mg; 0.16 mmol), Pd(PPh3)4 (37 mg; 0.032 mmol) and (1H-indazol-4-yl)boronic acid (52 mg; 0.32 mmol) are mixed in microwave vial (2-5 mL). The vial is capped with a septum, 2.0 mL of DME is added and the reaction mixture is immediately flushed with argon. Sodium carbonate solution (0.20 mL; 2M) is added and the mixture is flushed again with argon. The vial is re-capped with Teflon cap and irradiated in microwave for 15 min at 110° C. The mixture is cooled, diluted with EtOAc and filtered through Celite™, the Celite™ is rinsed 3× with EtOAc/MeOH (1:1). The filtrates are concentrated and deposited on silica. Purification by column chromatography on silica gel (pre treated with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc, and then to 50% MeOH in EtOAc lead to the isolation of the product as a yellow oil (28 mg; 31% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].I.[CH3:16][N:17]1[CH2:21][C:20](=[O:22])[N:19]=[C:18]1SC.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[N:17]([CH3:16])[CH2:21][C:20](=[O:22])[N:19]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC1=NC(=O)CN1C
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC2=NC(=O)CN2C)o1

Procedure:
2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethylamine (2.25 g), 1-methyl-2-methylthio-imidazolin-4-one hydroiodide (2.85 g) and triethylamine (3.635 g) were refluxed in ethanol (25 ml) for 4 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>ClCCl>[CH3:20][O:19][C:17](=[O:18])[CH:13]([NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Step 1A [Intermediate 1] To a dry round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (12.2 g, 47.7 mmol, 1 equiv.), anhydrous methylene chloride (170 mL), and H-D-Val-OMe (8.0 g, 47.7 mmol, 1 equiv.). The mixture was cooled to 0° C. in an ice bath followed by the addition of Hunig base (19.11 mL, 109.7 mmol, 2.3 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, solvent evaporated to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester in 96% yield (16.0 g). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 3.49 (s, 3 H) 3.74 (d, J=14.40 Hz, 1 H) 5.10 (d, J=9.85 Hz, 1 H) 7.66 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>>[CH:20]1([CH2:19][N:3]2[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:6]([CH3:7])=[C:2]2[CH3:1])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Reactant: BrCC1CC1
Product: Cc1cc(C(=O)CCc2ccccc2)n(CC2CC2)c1C
Yield: 93 %

Procedure:
The title compound was prepared as an orange oil in 93.0% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and bromomethylcyclopropane.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[C:8]1C=CC=CC=1.[N:21](OCCC(C)C)=[O:22]>C(O)(C)(C)C>[O:14]=[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[N:21][OH:22]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(C=NO)c1ccccc1

Procedure:
A flask was charged with potassium tert-butoxide (58 mmol) and 63 mL of tert-butyl alcohol. The mixture was stirred until a solution was formed, and a solution of the appropriate benzophenone (50 mmol) in 35 mL of tert-butyl alcohol added dropwise over 15 min. The reaction mixture was stirred for 1 hr, and the neat isoamyl nitrite (75 mmol) added over five min. The reaction mixture was monitored for completion and then diluted with 100 mL of heptanes. The resulting solid (38 mmol) was collected via suction filtration and dried to a constant weight under vacuum. Procedure was adapted from: Hagedorn et al., Chem. Ber., 98:193 (1965).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=2)[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:35])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]3)[CH:20]=2)=[N:8]1>C1(C)C=CC=CC=1>[NH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH2:28][CH2:27][C:26]([NH:25][C:21]2[CH:20]=[C:19]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=4)[NH:7][N:8]=3)[CH:24]=[CH:23][CH:22]=2)=[O:35])[CH2:30]1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)CCC3CCCNC3)c1)nn2C1CCCCO1
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)CCC4CCCNC4)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
1-Perhydro-2H-pyran-2-yl-3-[3-(3-piperidylpropanoylamino)phenyl]-1H-indazole-5-carboxamide was suspended in 20 mL of toluene and HCl gas was bubbled through for 15 min. The reaction mixture became gummy and was stirred at room temperature overnight. The supernatant solution was decanted and the residue was purified by preparatory HPLC. (0.017 g, 7% yield over 2 steps): 1H NMR (DMSO d6) δ 13.48 (s, 1H), 10.38 (s, 1H), 8.62 (s, 1H), 8.1 (s, 1H), 7.94 (dd, 1H), 7.94 (dd, 1H), 7.73 (d, 1H), 7.62 (d, 1H), 7.48 (t, 1H), 7.36 (br s, 1H), 2.65 (m, 2H), 2.5 (m, 2H), 2.4 (br s, 4H), 1.52 (m, 4H), 1.40 (m, 2H); ES-MS (m/z) 392 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:16]([N:19](C(C)C)C#N)(C)C>C1C=CC=CC=1.CCCCCC>[C:16]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)#[N:19]
Reactant: CC(C)N(C#N)C(C)C
Reactant: c1cnc2c(c1)CCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: N#CC1CCCc2cccnc21
Yield: 71 %

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (6.5 ml, 50 mM) in benzene (35 ml) maintained below 10° was treated with 1.6M butyl lithium in hexane (31.25 ml, 50 mM). The resulting anion solution was heated to reflux then treated with a solution of diisopropylcyanamide (6.3 g, 50 mM) in benzene (15 ml). After 15 min. the mixture was cooled and quenched with water (20 ml). The organic phase was separated, dried and evaporated. Distillation of the residue gave the title compound (5.6 g, 71%) Bp. 135°-140°/2 mm, identical with authentic material. Hydrochloride mp 185° C.--see Example 37 UK Pat. No. 1,432,378.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:26])[C:10]([C@@H:12]1[CH2:16][C:15]([F:18])([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:18][C:15]1([F:17])[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:8])[CH3:26])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 mL of trifluoroacetic acid was added under ice cooling to a 40 mL chloroform solution of 3.85 g of the compound obtained in step 3-4, and the reaction mixture was stirred for 2 hours at room temperature. The solvent was then distilled off under reduced pressure to obtain 8.02 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:31][C:28]1[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:26][C:25]([NH:24][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:30][N:29]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 4, 0.0895 g, 0.286 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2, 0.0772 g, 0.348 mmol) in THF (1 mL) in 5 mL microwave vial, LiHMDS (1.14 mL, 1.14 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding saturated aqueous sodium chloride (0.2 mL). The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken into THF (5 mL) and 5 N HCl (1 mL) was added. The yellow mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The pure fractions were collected and lyophilized to afford N-(2-chloro-5-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (TFA salt, 0.0185 g, 11% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1H) 9.79 (d, J=7.63 Hz, 1H) 9.67 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (s, 1H) 8.50 (d, J=2.54 Hz, 1H) 8.41 (dd, J=4.69, 1.96 Hz, 1H) 7.14 (dd, J=7.92, 4.79 Hz, 1H) 3.13-3.18 (m, 3H) 2.86-2.90 (m, 3H). Note: one proton was missing from the NMR spectrum. m/z (ESI, positive ion): 430.9 (M+H)+ as parent ion.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[CH:2]1([N:8]([OH:9])[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: ONC1CCCCC1
Agent: Cl
Product: CSc1ccc(NC(=O)N(O)C2CCCCC2)cc1
Yield: 21.4 %

Procedure:
Using the general method of Compound 1, N-cyclohexylhydroxylamine hydrochloride (1.5 g, 10 mmol) was reacted with 4-(methylthio)phenyl isocyanate (1.6 g, 10 mmol) to provide 0.60 g of the desired product as a white solid m.p. 151°-153° C. Analysis: Calculated for C14H20N2O2S: %C, 59.97; %H, 7.19; %N, 9.99; Found: %C, 60.06; %H, 7.14; %N, 9.95.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:28][CH:27]=1)([CH2:15][O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: BrCCCCCCc1ccccc1
Reactant: CC(=O)NC(CCc1ccc(C=O)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Product: CC(=O)NC(CCc1ccc(C(O)CCCCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Yield: 65.2 %

Procedure:
2-Acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-formylphenyl)ethyl)propane (3.0 g) and 1-bromo-6-phenylhexane (3.1 g) were reacted and treated in the same manner as in Working example 1(6) to give the title compound (2.6 g) as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CN[C@H]1[C@H](NC)CCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:9]2[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH:35]=[CH:34][N:33]=[CH:32]3)=[CH:3][CH:4]=2)=[CH:25][CH:26]=1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
A reaction tube charged with 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (100.0 mg, 0.209 mmol), imidazole (85.5 mg, 1.26 mmol), Cul (4.0 mg, 0.021 mmol), (1R, 2R)-diaminomethylcyclohexane (6.0 mg, 0.042 mmol), and K3PO4 (88.9 mg, 0.429 mmol) is purged with nitrogen. Anhydrous 1,4-dioxane (4.0 mL) is added via syringe. The reaction mixture is heated at 100° C. for 5 days, and is partitioned between saturated NH4Cl aqueous solution and ethyl acetate. The organic phase is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography to provide the title compound (78.7 mg, 81% yield) as a white solid product; 1HNMR (CDCl3, 400 MHz) δ 8.91 (s, 1H), 8.35 (s, 1H), 8.10 (dd, 2H), 7.59 (d, 2H), 7.52 (m, 3H), 7.44-7.36 (m, 6H), 7.13 (d, 2H); HPLC-MS calculated for C26H17ClN6O (M+H+) 465.1. Found: 465.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-methoxyphenyl isocyanate in a similar manner as described above to give a gray solid (61% yield). 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 8.16 (s, 1H), 7.60 (d, 1H), 7.38-7.27 (m, 3H), 7.17 (dd, 1H), 6.87 (d, 2H), 6.52 (d, 1H), 5.01 (m, 1H), 3.73 (s, 3H), 2.67 (m, 2H), 2.04 (m, 1H), 1.94-1.76 (m, 3H); MS m/z 414 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:37][NH2:38]>C(Cl)Cl>[OH:37][NH:38][C:14](=[O:15])[CH2:13][CH:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1OC
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(SC(CC(=O)NO)Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (6.02 mmol) of 3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutanoic acid in 50 mL of CH2Cl2 at 25° C. under argon is added 0.2 mL of DMF followed by 6.02 mL (12.03 mmol, 2 eq) of 2 M solution of oxalyl chloride in CH2Cl2. After stirring at 25° C. for 3 hours, the mixture is cooled to 0° C. and 3.7 mL (30.08 mmol, 5 eq) of O-trimethylsilylhydroxylamine is added. This mixture is then stirred at 25° C. for 18 hours. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The product is purificatied by flash silica gel chromatography to afford N-hydroxy-3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutyramide as a yellow crystalline solid. (1.7 g, 81%): 1H-NMR (300 MHz, DMSO-d6) δ (TMS) 2.2(m, 2H), 2.81 (m, 2H), 3.6(m, 1H), 3.75(s, 6H), 6.89-7 (m, 3H), 7.17-7.35(m, 5H), 8.85(s, 1H), 10.5(s, 1H).