Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]([CH2:37][CH2:38][O:39][CH3:40])=[C:35]=[S:36]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:35]([NH:34][CH2:37][CH2:38][O:39][CH3:40])=[S:36])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COCCN=C=S
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Solvent: O
Solvent: C1CCOC1
Product: COCCNC(=S)Nc1nc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc2n1
Temperature: 60 °C
Yield: 2.4 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol), obtained in Example B19, and 1-isothiocyanato-2-methoxy-ethane (3 equiv, 0.00063 mol) in THF (1 ml) was heated at 60° C. for 5 hours. A few drops of water were added. The mixture was evaporated till dryness and purified by HPLC. The pure fractions were collected and the solvent was evaporated, yielding 0.003 g (2.4%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-N′-(2-methoxyethyl)-thiourea, MS(ESI) m/z: 593 595 597.
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])C>>[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([OH:8])=[O:2]
Reactant: CCC(C(=O)O)c1ccc(C(C)=O)cc1
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of sodium hypochlorite (330 mL, 17.32 g, 0.234 mol) in a solution of sodium hydroxide (50%, 172 mL), warmed to 55° C., was added, portionwise as a solid, 4-acetylphenylbutyric acid (16.0 g, 0.078 mol) while keeping the temperature between 60°-70° C. All was stirred at 55° C. over 20 hours. The cooled solution was quenched by the dropwise addition of a solution of sodium bisulfite (25%, 330 mL). The mixture was then transferred to a beaker and acidified by the careful addition of concentrated hydrochloric acid. The resulting solid was collected, washed with water and dried, then triturated sequentially with chlorobutane and hexane to give 4-carboxyphenylbutyric acid (15.31 g, 0.074 mol, 95%) as a white solid. mp=190°-195° C.; 1H NMR (DMSO) d 12.55 (bs, 1H), 8.1 (s, 1H), 7.85 (d, 2H, J=8.1 Hz), 7.3 (d, 2H, J=8.1 Hz), 2.7 (t, 2H, J=7.5 Hz), 2.2 (t, 2H, J=7.4 Hz), 1.8 (quintet, 2H, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>>[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])[CH2:27][C:26]([O:25][CH3:24])=[O:31]
Reactant: COC(=O)CC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)CC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethyny-octahydro-indole-1-carboxylic acid methyl ester and malonic acid monomethyl ester to yield (3aR,4S,7aR)-1-(methoxycarbonyl)-4-(m-tolylethynyl)octahydro-1H-indol-4-yl methyl malonate. MS [M+H]=414; RT=1.24 min; UPLC Method I
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[OH:11].Cl[C:15]([F:20])([F:19])C([O-])=O.[Na+].[OH-].[Na+].Cl>O.CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][CH:15]([F:20])[F:19]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CON(C)C(=O)c1cccnc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cccnc1OC(F)F
Temperature: 25 °C
Yield: 53.2 %

Procedure:
N-methoxy-N-methyl-2-hydroxynicotinamide (500 mg, 2.76 mmol), sodium chlorodifluoroacetate (505 mg, 3.31 mmol), and sodium hydroxide (132 mg, 3.31 mmol) were added to N,N-dimethylformamide (1.4 mL). The resultant mixture was stirred at 125° C. overnight under an argon atmosphere. The reaction solution was cooled down to room temperature, added with 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (chloroform/methanol=9/1). N-methoxy-N-methyl-2-difluoromethoxynicotinamide (341 mg, yield 53%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[N:22][C:23]=3[CH2:24][O:25]2)=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[N:22][C:23]=3[CH2:24][O:25]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OCc1nnccc1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nnccc1-2
Reaction time: 96 h
Yield: 53.8 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.631 g) was added to a solution of methyl 7-amino-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 6, 0.395 g) in pyridine (20 mL) and DCM (20 mL) and the mixture was allowed to stand at room temperature for 4 days. The resulting solution was evaporated in vacuo, and the residue was partitioned between a mixture of DCM and water and filtered through a phase separator. The filtrate was evaporated to dryness, and the residue was azeotroped with toluene. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-10H-9-oxa-1,2-diaza-phenanthrene-8-carboxylate (0.408 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5]C)=[O:3].[CH3:7][C:8]1([CH3:18])[CH2:13][C:12]([CH2:15][NH2:16])([CH3:14])[CH2:11][CH:10](N)[CH2:9]1>>[CH3:5][O:4][C:2]([NH:16][CH2:15][C:12]1([CH3:14])[CH2:13][C:8]([CH3:18])([CH3:7])[CH2:9][CH:10]([NH:1][C:2]([O:4][CH3:5])=[O:3])[CH2:11]1)=[O:3]
Reactant: CCOC(N)=O
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Product: COC(=O)NCC1(C)CC(NC(=O)OC)CC(C)(C)C1
Yield: 98.1 %

Procedure:
The thus-prepared crude reaction solution was analyzed by gas chromatography and it was confirmed that a urethane compound corresponding to IPDA, that is, 3-methoxycarbonylaminomethyl-3,5,5-trimethyl-1-methoxycarbonylaminocyclohexane, was produced in a yield of 98.1% based on IPDA.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19](Cl)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(C(=O)Cl)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cn1c(C(=O)N2CCCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A suspension of the acyl chloride 219 (700 mg, 1.617 mmol) and pyrrolidine (0.3 mL, 3.63 mmol) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was triturated with ether to give title compound 220 (756 mg, 1.617 mmol, 100% yield) as beige solid. MS: 468.3 (MH+).
Reaction SMILES: [Cl-].[C:2]([C:5]1([NH3+:8])[CH2:7][CH2:6]1)([OH:4])=[O:3].C(N(CC)CC)C.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>CO>[F:16][C:17]([F:24])([F:23])[C:18]([NH:8][C:5]1([C:2]([OH:4])=[O:3])[CH2:7][CH2:6]1)=[O:19]
Reactant: CCOC(=O)C(F)(F)F
Reactant: [NH3+]C1(C(=O)O)CC1
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Carboxycyclopropanaminium chloride (0.980 g, 7.124 mmol) was suspended in methanol (14 mL) and triethylamine (1.514 g, 14.960 mmol) was subsequently added. To this suspension was then added ethyl trifluoroacetate (1.113 g, 7.836 mmol) and allowed to stir at 25° C. After 16 hours, the reaction was quenched with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried with sodium sulfate, filtered and concentrated under reduced pressure to produce the title compound as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.76 (s, 1H), 9.94 (s, 1H), 1.38-1.44 (m, 2H), 1.08-1.14 (m, 2H).
Reaction SMILES: O.NN.Cl.[NH:5]1[CH2:9][CH2:8][N:7]=[C:6]1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([N+:20]([O-])=O)=[CH:15][CH:16]=2)[CH2:11]1>[Ni].C(O)C>[NH:7]1[CH2:8][CH2:9][N:5]=[C:6]1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([NH2:20])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(C1=NCCN1)CC2
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CN(C1=NCCN1)CC2
Reaction time: 2 h

Procedure:
2 ml of hydrazine hydrate are added at 40° C. to a suspension of 2 g of the hydrochloride of the product obtained in Step 1 and 2 g of Raney nickel in 50 ml of ethanol. After 2 hours at 50° C., the catalyst is filtered off and the solvent is evaporated off.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9].[CH2:12](Br)[CH:13]=[CH2:14].O>CN(C)C=O>[CH3:9][C@H:8]([O:10][CH2:14][CH:13]=[CH2:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:11])[CH3:3]
Reactant: CC(C)CCC[C@H](C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO[C@@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72 mmol) and dimethylformamide (100 mL) were charged to a 250 mL three-necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added a solution of (2S)-6-methylheptan-2-ol (3.1 g, 24 mmol) in dimethylformamide (10 mL). This reaction mixture was stirred at room temperature for 1 hr then allyl bromide (8.6 g, 72 mmol) was added dropwise over 10 minutes ensuring the reaction temperature did not rise significantly (41° C. was observed). The reaction mixture was stirred for a further 20 minutes until the reaction was complete. To the reaction mixture was added water (10 mL) and the resultant mixture was extracted with methyltert-butyl ether (2×100 mL). The combined organic phase was dried over magnesium sulphate and the solvent remove in vacuo to yield a yellow oil which was chromatographed over silica gel (hexane/methyltert-butyl ether) to give 3-{[(1S)-1,5-dimethylhexyl]oxy}prop-1-ene as a sl. yellow oil (2.7 g, 15.8 mmol, chemical yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]CC.[Na+].[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=[CH2:23].Cl>C(O)C.O>[O:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH:6]([C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: C=CC(=O)CCCCCCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 0.91 g of ethyl 2-chlorobenzoylacetate in 10 cc of ethanol was added 0.27 g of sodium ethoxide at room temperature, and the mixture was stirred at room temperature for 10 minutes. Then, 0.62 g of 3-oxo-1-decene in 10 cc of ethanol was added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the aqueous layer was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane =1/9) to obtain 0.90 g of compound I. Yield: 59.1%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:23]([NH2:37])=[N:24][CH:25]=[C:26]([C:2]2[S:6][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:27]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)s1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cnc(N3CCOCC3)s2)cc1-c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-morpholine (0.0600 g, 0.241 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.110 g, 0.313 mmol), potassium carbonate (0.106 g, 0.771 mmol), and Pd(PPh3)4 (0.02 g, 0.02 mmol) in previously degassed DME/Water (4:1) (2.7 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor at 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic extracts were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was submitted for MDP for purification. The pure fractions were combined and the organic was concentrated in vacuo then diluted with CHCl3 and neutralized with sat. NaHCO3. The layers were separated, and the aqueous layer was re-extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.44 (d, J=5.1 Hz, 4H), 3.73 (d, J=5.1 Hz, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.61 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.03 (br. s., 2H), 8.10 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H). MS (ES+): m/z=396.07 (100) [MH+]. HPLC: tR=3.57 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:21]1[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]1[O:23]C(=O)C.[NH3:39]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][O:11][C:9]2[N:10]=[C:2]([NH2:39])[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=2)[C@@H:21]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]2[OH:23])=[CH:15][CH:16]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Solvent: CCO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 100 °C
Yield: 99 %

Procedure:
A reactor was charged with 6-chloro-2-[2-(4-chlorophenyl)ethoxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (243.8 g, 0.43 mol, Example 2, Step D) in ethanol (3,660 mL). The reactor was chilled to below −33° C., and ammonia (1500 g) is charged into the reactor. The reactor was sealed, then heated to 100° C. and the reaction was monitored by HPLC. Upon completion (approximately 5 hours), the reactor was cooled, vented, and the contents concentrated under reduced pressure. The crude product is purified by column chromatography eluting with dichloromethane/methanol. The pure fractions were concentrated under reduced pressure to about four liters of solvent and the product collected by vacuum filtration. The off-white solid was washed with dichloromethane and dried in vacuo to yield 82 grams of analytically pure (>99%) product as an off-white solid. Additional fractions were combined to provide an additional 73 g of product of lower purity (90-98%). Combined typical yield: 54%.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.Br[CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:34]1([CH2:33][N:13]2[CH:12]=[C:11]([C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]5[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=6[NH:24][C:23]5=[O:31])[CH2:20][CH2:21]3)[N:6]=[CH:5][N:4]=4)[CH:15]=[N:14]2)[CH2:37][CH2:36][CH2:35]1
Reactant: Cn1c(-c2cn[nH]c2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: BrCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cnn(CC3CCC3)c2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 20.7 %

Procedure:
To a solution of 1-{1-[9-methyl-8-(1H-pyrazol-4-yl)-9H-purin-6-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (30 mg, 0.07 mmol) in DMF (0.5 mL) were added (bromomethyl)cyclobutane (0.02 mL, 0.18 mmol), and sodium bicarbonate (9 mg, 0.11 mmol). The reaction mixture was heated to 100° C. for 24 hours. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 7 mg (23% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.01 (t, 1H), 7.13 (dd, 1H), 6.95-6.90 (m, 3H), 4.62-4.45 (m, 1H), 4.21 (d, 2H), 3.86-3.82 (m, 3H), 2.79 (dt, 1H), 2.40-2.25 (m, 2H), 2.01-1.92 (m, 2H), 1.87-1.70 (m, 6H); MS (EI) for C26H29N9O: 484.5 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:3]4[C:4]([C:5]#[N:6])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=4[F:1])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1ccc(F)c(F)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(C#N)ccc(F)c4F)ncnc32)CC1
Temperature: 160 °C
Yield: 17.2 %

Procedure:
A mixture of 3,4-difluoro-2-hydroxy-benzonitrile (Oakwood Products, Inc., West Columbia, S.C., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (7 mg, 17%) as a white solid. Mass spectrum MH+=457.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][CH:19]=[O:20])[CH3:2].[CH3:21][Mg]Br.CCOCC>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH2:18][CH:19]([OH:20])[CH3:21])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(C)O
Temperature: 0 °C
Yield: 70 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetaldehyde (0.253 g, 0.840 mmol), is dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. with stirring under nitrogen. Methylmagnesium bromide, 3.0M in ether, (0.300 mL, 1.00 mmol) is added and the ice bath removed. After slowly warming to room temperature, the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is quenched with saturated ammonium chloride solution and diluted with ether. The two phases are separated and the organic washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The 1-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-2-ol (0.222 g, 0.7049 mmol) is formed in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:13]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Cl)nc1
Yield: 69 %

Procedure:
6-chloropyridine-3-sulfonyl chloride (4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (150 mL) and any insoluble material filtered. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted with EtOAc (1×15 mL). The combined EtOAc extractions were washed with H2O (1×50 mL) and saturated NaCl (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give 6-chloropyridine-3-sulfonamide (2.58 g, 69%). MS (EI) m/z for C5H5Cl2N2O2S: 190.9 (MH+).