Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14](C(O)=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=[C:53]([O:55]C)[N:52]=[C:51]([N+:57]2(C)[CH2:62][CH2:61]OCC2)[N:50]=1.S(O)(O)(=O)=O.N1C=CN=C1N>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:53]([NH:52][C:51]3[NH:50][CH:61]=[CH:62][N:57]=3)=[O:55])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ncc[nH]2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (121 mg, 0.225 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.087 mL, 0.788 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (89 mg, 0.270 mmol). The solution was stirred for 15 min, and then 1H-imidazol-2-amine sulfate (38.7 mg, 0.293 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated and the residue was purified by RP-HPLC to provide phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(1H-imidazol-2-ylamino)carbonyl]-1-pyrazolidinecarboxylate as a colorless gum (39 mg, 29%)
Reaction SMILES: [C:1]1([PH:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:20][C:21]([CH3:23])=[O:22]>>[C:1]1([P:7]([C:21]([OH:22])([CH3:23])[CH3:20])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (202 g) diphenyl phosphine oxide (DPPO) and 500 ml THF were added. The mixture was heated to 70° C. and then stirred. The stirring was continued until DPPO was dissolved completely. To this solution was added slowly 1.0 mole (58 g) acetone within two hours, and the temperature thereof was maintained at 70° C. for six hours after the addition of acetone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenyl phosphoryl) propan-2-ol [DPPP]. Yield, 96%; m.p. 96-98° C. Anal. Calcd. for C15H17PO2: C, 69.23; H, 6.53; O, 12.31; P, 11.93. Found: C, 69.11; H, 6.63; O, 12.18; P, 12.08. EIMS, m/z: 260 (96. M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([C:28]([OH:30])=O)[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:37]C=2C=1.C(Cl)CCl.[NH4+].[OH-]>C(Cl)Cl.CN(C=O)C.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([C:28](=[O:30])[NH2:37])[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(=O)O)cc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Reaction time: 0.5 h
Yield: 333.4 %

Procedure:
To 9-tert-butoxycarbonylamino-3-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (1.5 g, 3.60 mmol) in CH2Cl2/DMF (4:1, 25 mL) was added HOBT (0.53 g, 4.0 mmol) and EDC (0.76 g, 4.0 mmol) and the mixture allowed to stir for 30 min. To this was added NH4OH (27% aqueous, 0.30 mL, 4.0 mmol) and stirring was continued for 3 h. The mixture was diluted with 1 M HCl and extracted with EtOAc. The combined extracts were washed with water, sat'd NaHCO3, dried over magnesium sulfate,and concentrated to a solid. The solid was recrystallized from Et2O to yield a white solid (5.0 g, 68%). MS [M−H]− 415, m.p. 193-194° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[NH:17][N:16]=1.O[CH2:26][CH:27]1[CH2:30][CH2:29][N:28]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH2:26][CH:27]3[CH2:30][CH2:29][N:28]3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3F)c12
Reactant: CC(C)(C)OC(=O)N1CCC1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.4 %

Procedure:
To a mixture of 3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.930 mmol), tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (0.33 mL, 1.9 mmol) and PPh3 (733.86 mg, 2.8 mmol) in THF (10 mL) in ice bath, the DIAD (0.37 mL, 1.87 mmol) as a solution in 5 ml THF was slowly added. The mixture was stirred at RT overnight and then the solvent was removed. To the residue was added H2O and the mixture was extracted with EtOAc. The combined organic layer was washed with NaHCO3, then brine, and dried over Na2SO4. The solvent was removed to get tert-butyl 2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate weighing 800 mg, which was used without further purification for the next step.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:17]4=3)[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:28]>C(O)C.[Pd]>[ClH:28].[CH3:26][C:24]1([CH3:27])[O:25][C:16]2[C:17](=[C:18]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]2[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]3=2)[CH2:22][CH2:23]1
Reactant: CC1(C)C=Cc2c(ccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)O1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CCc2c(ccc3[nH]c4c(c23)CCNCC4)O1
Yield: 30.8 %

Procedure:
A solution of 10-benzyl-3,3-dimethyl-7,8,9,10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole (0.065 g, 0.18 mmol, Example 11) in ethanol (20.0 mL) was hydrogenated in the presence of palladium on carbon (0.035 g) and 2 N hydrochloric acid (0.09 mL, 0.1 8 mmol) at 55 psi for 3 days. Palladium on carbon (0.035 g) was added and continued hydrogenation for another 4 days. After filtration through a pad of celite, the filtrate was concentrated in vacuo to dryness. The residue was recrystallized from EtOAc/MeOH to give 0.017 g (30%) of colorless solid as the desired product: mp>258° C. (dec.); 1H NMR (300 MHz, MeOH-d4) δ 7.00, 6.52, 3.47, 3.22-3.13, 1.89-1.85, 1.33; MS (ESI+) m/z 271 (M++H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N[C:16]1([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:18][CH2:17]1)CCC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu].[Cu]Cl>[CH2:10]([N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:28][CH:29]=2)=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCNC1(NCCCC)C=CC(CCc2ccc(N)cc2)=CC1
Agent: Cl[Cu]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Yield: 18.6 %

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (1.46 g, 9.36 mmol), 4-[2-(4,4-dibutylaminophenyl)ethyl]phenylamine (3.31 g, 10.20 mmol), anhydrous potassium carbonate (4.27 g, 30.88 mmol), copper powder (1.25 g, 19.65 mmol), and copper(I) chloride (0.092 g, 0.93 mmol) in dry DMF (30 mL) using the procedure described in Example 1, Step C, Method B. This procedure yielded a 0.39 g (0.87 mmol, 8.6%) of the desired product. mp 115-117° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[N:23]=[C:22]([CH2:24][CH2:25][C:26]4[N:31]=[C:30]([NH2:32])[CH:29]=[C:28]([CH3:33])[CH:27]=4)[NH:21][C:18]3=[N:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:32][C:30]1[N:31]=[C:26]([CH2:25][CH2:24][C:22]2[NH:21][C:18]3=[N:19][CH:20]=[C:15]([C:11]4[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=4)[CH:16]=[C:17]3[N:23]=2)[CH:27]=[C:28]([CH3:33])[CH:29]=1
Reactant: Cc1cc(N)nc(CCc2nc3cc(-c4cccc(OCc5ccccc5)c4)cnc3[nH]2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cccc(O)c4)cnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 22.9 %

Procedure:
110 mg of 6-{2-[6-(3-benzyloxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine (compound 13) and 33 mg palladium on active carbon (10% Pd) are suspended in 12 ml of methanol. The suspension is vigorously stirred at r.t. for 64 h under a hydrogen atmosphere. The suspension is passed through kieselguhr and rinsed with methanol. The filtrate is concentrated to dryness to afford 53 mg of crude product. Purification by HPLC yields 20 mg of the title compound as a colorless solid. M.p. 162° C. ESI-MS: 346.2 (MH+). TLC: Rf=0.17 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:16]
Reactant: NN
Reactant: FC(F)(F)c1nc2c(Cl)nccc2[nH]1
Solvent: CCO
Product: NNc1nccc2[nH]c(C(F)(F)F)nc12

Procedure:
A mixture of 132 mg (0.6 mmol) of 4-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine, 0.0787 mL (2.4 mmol) of anhydrous hydrazine, and 3 mL of ethanol was stirred at reflux for 2 days. The cooled, filtered solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to yield the title compound. LC-MS 218 (M+1).
Reaction SMILES: F[B-](F)(F)F.ClC1C(C)=CC=C[N+]=1CC.O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C>C(#N)C>[CH2:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[O:33][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: CC[n+]1cccc(C)c1Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 78 %

Procedure:
To a refluxing solution of 486 mg (2.0 mmol) of 2-chloro-1-ethyl-3-methylpyridinium tetrafluoroborate in 50 ml of acetonitrile, there was added a solution of 129 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 78% yield.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([O:18]C)=[O:17].[OH-].[Na+].Cl>C(O)C.O>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)Cc1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)Cc1ccccc1CO2

Procedure:
Dissolve 1.4 gm of the ester of Step A in 15 ml of ethanol and add 15 ml of 20% aqueous sodium hydroxide. Warm gently on a steam bath until complete solution is obtained. Strip to dryness and dissolve in water. Acidify with concentrated hydrochloric acid and separate the precipitate by filtration. Crystallize from methanol to obtain the title product (m.p. 240°-244° C.)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O>[CH:8]1[CH:7]=[C:3]2[C:4]([N:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Solvent: O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 200 °C

Procedure:
A mixture of phthalic anhydride (500 g) and β-alanine (267 g) was fused by heating at 200° C. for 15 minutes, and poured into water (1500 ml). The formed precipitate was collected by filtration, and recrystallized from ethanol to give phthaloyl-β-alanine (hereinafter referred to as pht-βAla), yield 537 g, 81.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:17]=[C:16]([NH:18][O:19]C3CCCCO3)[C:15]3[C:14]([CH3:26])=[N:13][C:12]([NH2:27])=[N:11][C:10]=3[CH2:9]2)=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=2)[CH:3]=1.Cl>O1CCOCC1>[NH2:27][C:12]1[N:13]=[C:14]([CH3:26])[C:15]2=[C:10]([CH2:9][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[NH:17]/[C:16]/2=[N:18]\[OH:19])[N:11]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
(7R)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.891 g, 1.86 mmol) was dissolved in 10 mL of dioxane. 4M of HCl in dioxane (1.86 mL, 7.45 mmol) was then added slowly to the above stirred solution. After all the HCl was added, a yellow solid was formed at the bottom of the reaction flask. The deprotection was allowed to go for 30 minutes, then the supernatant was decanted. Dichloromethane was added to wash the solid, then it was decanted. This process was repeated a few times. No product was found in the dioxane and dichloromethane washes. The solid product was then purified on flash column chromatography, SiO2, gradient 2-15% methanol/chloroform to give 0.404 g of product, 63.5% yield over 2 steps. MS (ES) [M+H] calc'd for C20H19FN6O2, 395. found, 395.3. 1H NMR (400 MHz, METHANOL-d4) δ 2.60 (s, 3H), 3.09-3.19 (m, 1H), 3.29-3.34 (m, 1H), 3.91 (s, 3H), 5.45 (br. s., 1H), 6.82 (d, J=8.34 Hz, 1H), 7.16 (d, J=6.57 Hz, 1H), 7.19-7.30 (m, 2H), 7.55 (dd, J=8.59, 5.56 Hz, 1H), 7.79 (dd, J=8.34, 7.33 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[CH3:13][C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=[C:17](N)[C:16]=2[CH:15]=1>CN1C(=O)CCC1.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[NH:8][CH2:9][CH2:10][N:11]([C:17]2[C:16]3[CH:15]=[C:14]([CH3:13])[S:23][C:22]=3[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=2)[CH2:12]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: COCCCC[C@H]1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Temperature: 211 °C

Procedure:
Heat in a 211° C. oil bath, a stirring solution of (S)-2-(4-methoxybutyl)-piperazine 0.086 g, 0.49 mmol), and 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.114 g, 0.49 mmol) in NMP (1 mL) for 4 h. Cool to room temperature, dilute the solution with brine (15 mL) and extract with EtOAc (3×30 mL). Concentrate the organic layers under reduced pressure to a volume of 20 mL and wash with 75% brine (4×20 mL). Dry the organic layer over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 10% (33% 2 M NH3 in MeOH/64% EtOH)/CH2Cl2. Combine the purified fractions, concentrate under reduced pressure, azeotrope with CH2Cl2/hexanes and place under vacuum to give the title compound: brown solid (0.036 g), mass spectrum (m/e):385.08 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 90.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (98.0 mg, 0.159 mmol) prepared in Example 167c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (67.0 mg, 90%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11]Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O-:26])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14].[Cs+].[I-].[Na+]>CN(C=O)C>[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O:26][CH2:11][O:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(Cc1ccccc1)OCCl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)Cc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Reaction time: 4 h

Procedure:
Chloromethyl phenylacetate (1.0 2 g, 5.5 mmol) (Intermediate 4) in dry DMF (50 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (3.80 g, 5.0 mmol) and sodium iodide (37 mg, 0.25 mmol) in dry DMF (70 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (50 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2([NH:31]C(=O)C)[CH2:28][O:27]C(C)(C)[O:25][CH2:24]2)=[CH:17][CH:16]=1.[ClH:35]>CO>[ClH:35].[NH2:31][C:23]([CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][C:2]=2[F:1])=[CH:20][CH:19]=1)([CH2:28][OH:27])[CH2:24][OH:25]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccccc4)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CO
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Sc3ccccc3)cc2F)cc1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
N-(5-{2-[2′-Fluoro-4′-(phenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (468 mg) was dissolved in methanol (6 mL), concentrated hydrochloric acid (3 mL) was added, and the mixture was stirred at 70° C. for 3.5 hr. The reaction mixture was concentrated, and the residual crude crystals were suspended in diisopropyl ether and collected by filtration to give the title compound (329 mg) as white crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]5[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=5)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]5[O:31][C:30]([CH2:32][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:29][CH:28]=5)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cc2F)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cc2F)o1

Procedure:
Prepared according to Procedure D from 5-(4-(4-Phenylsulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR (400 MHz, DMSO-d6) δ: 10.38 (s, 1H), 8.87 (d, 1H), 8.62 (s, 1H), 8.11 (d, 2H), 7.95 (m, 4H), 7.63 (m, 4H), 6.94 (m, 1H), 6.51 (d, 1H), 3.84 (s, 2H), 3.25 (m, 2H), 2.98 (s, 3H), 2.95 (m, 2H). ESI-MS m/z 579 (M−1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:9].Cl>CN(C=O)C.O>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH3:9]
Reactant: CCOC(=O)COCCCCBr
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCCNS(C)(=O)=O
Temperature: 100 °C
Yield: 17.1 %

Procedure:
To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5 mL). The mixture was heated at 100° C. for 1.5 h and was cooled to room temperature. A solution of (4-bromo-butoxy)-acetic Acid ethyl ester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction was heated at 100° C. for 21 h. Water was added to the cooled reaction mixture and the aqueous solution was acidified to pH=2 with concentrated HCl. The aqueous solution was extracted with EtOAc (4×) and the organic solution was dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography (60% EtOAc/hexanes) to afford the title compound (181 mg). 1H NMR (400 MHz, CDCl3) δ 4.90 (m, 1H), 4.20 (q, 2H), 4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H), 1.26 (t, 3H); MS 254.1 (M+1).