Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2Br)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O1CCOCC1.[C:53]1(B(O)O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.13 mmol) in 10:1 dioxane:water (5 mL) was phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0.3 mmol), and PdCl2(dppf)-CH2Cl2 (6 mg, 0.007 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:10]([NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: COc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccccc1OC
Yield: 96.5 %

Procedure:
According to the general procedure B, 2-Chloroanisole (72 mg, 0.51 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(OAc)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 100° C. to give the title compound (102 mg, 97%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 6.93 (t, 1H, J=8.0 Hz, aryl coupling J=0.9 Hz), 6.82 (d, 1H, J=8.0 Hz), 6.66-6.73 (m, 2H), 4.30 (bs, 1H), 3.89 (s, 3H), 3.17 (t, 2H, J=7.2 Hz), 1.71 (m, 2H), 1.51-1.34 (m, 6H), 0.97 (t, 3H, J=6.4 and 6.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.65, 138.39, 121.23, 116.03, 109.71, 109.24, 55.29, 43.63, 31.63, 29.43, 26.88, 22.58, 14.00. GC/MS(EI): m/z 207 (M+). Anal. Calcd for C13H21NO: C, 75.23; H, 10.21; N, 6.76. Found: C,75.41; H, 10.25; N, 6.69.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: Oc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
728 g of 3-chloro-2-fluoroaniline was added to a reactor having 6,860 g of 30.6% sulfuric acid placed therein, followed by stirring for 30 minutes at 80° C. Thereafter, the mixture was cooled to −10° C., and 952 g of a 37.0% sodium nitrite aqueous solution was added dropwise thereto over 90 minutes in a temperature range of −10 to −5° C., followed by stirring for 30 minutes in that temperature range. The resulting reaction mixture was added to another reactor having 4,100 g of 51.2% sulfuric acid, 1,500 g of copper sulfate and 3,000 mL of toluene placed therein over 6 hours in a temperature range of 80 to 85° C., followed by stirring for 30 minutes in that temperature range. The resulting reaction mixture was cooled to a temperature range of 70 to 75° C. and left at rest to separate into two layers, i.e., an organic layer and an aqueous layer, and the organic layer was collected. The aqueous layer was cooled to 20° C., and copper sulfate was filtered off, followed by extracting with 1,200 mL toluene twice. The organic layer obtained by extraction was washed with 700 mL of water and subjected to fractional distillation to obtain 300 g of 3-chloro-2-fluorophenol (b5). The compound had a boiling point of 60 to 62° C./1 mmHg.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br.O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2nnc(-c3ccc(OC)cc3)s2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc(-c2nnc(-c3ccc(O)cc3)s2)nc1
Yield: 32.5 %

Procedure:
To 9.0 g of 2-(5-butyl-2-pyridyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole, 90 g of a solution of hydrogen bromide in acetic acid was added, followed by heating to 100° C. for 95 hours of reaction while gaseous hydrogen bromide was bubbled. After the reaction, the reaction mixture was poured into 1 liter of water to precipitate a crystal. The crystal was washed with water and recrystallized from a mixture solvent of ethanol/water=9/1 to obtain 2.8 g of an objective product.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:31]([CH3:33])[CH3:32])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:30])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:29])[CH2:21][CH2:22][C@H:23]([O:25]C(C)=O)[CH2:24][C:19]4=[CH:18][CH:17]=[C:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:1][CH2:2][C@@H:3]([CH:31]([CH3:32])[CH3:33])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:30])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:29])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH:17]=[C:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-dehydrositosterol acetate (6) (2.5 g, 5.5 mmol) in dry ether (200 mL) was added lithium aluminum hydride (2.09 g, 55.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then cooled with an ice-water bath and the excess water (5 mL). After 30 minutes, ether (100 mL) was added and filtered. The cake was washed with ether (2×100 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 7-dehydrositosterol (7) in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22])([O-])=O.O.O.[Sn](Cl)Cl.CCCCCC.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][C:5]=1[C:21]([F:23])([F:24])[F:22]
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])c(C(F)(F)F)c3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3ccc(N)c(C(F)(F)F)c3)sc2c1
Yield: 91.8 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(4-nitro-3-trifluoromethyl phenyl)-6-methoxybenzothiazole (1.0 g, 2.82 mmol) and tin (II) dichloride dihydrate (5.1 g, 22.6 mmol) in EtOH (50 ml) to give the title compound (0.84 g, 91%) as a pale orange solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>CO.C(Cl)Cl>[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: OCC1CCCN1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCCC3CO)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.169 mmol) with 2-hydroxymethylpyrrolidine (46 mg, 0.45 mmol) as described in General Procedure X to afford Iw (42.0 mg, 65.6%) as a tan solid, tlc Rf=0.15 (10% MeOH/CH2Cl2−0.25% Et3N), m/z obs=382 (M+1).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[N:10]=2)=[CH:4][C:3]=1[CH3:17]>Br.C(O)(=O)C.O>[I:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COc1nccc(-c2cc(C)c(I)c(C)c2)n1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc[nH]c(=O)n2)cc(C)c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-(4-Iodo-3,5-dimethylphenyl)-2-methoxypyrimidine is dissolved in 33% solution of HBr in acetic acid (7.7 mL) and the mixture is stirred for 12 hours at room temperature. Then the mixture is diluted with water. The formed precipitate is filtered off, washed with acetone and dried. Yield: 1 g; LC (method 11): tR=0.92 min; Mass spectrum (ESI+): m/z=327 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C@H:9]2[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[CH2:11][C@H:10]2[CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:3]1=[O:28].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:15]([C@@H:12]1[CH2:13][CH2:14][C@H:9]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=3)[C:3]2=[O:28])[C@H:10]([CH2:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH2:11]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H](N2CCCC[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CC[C@H](N2CCCC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 101 %

Procedure:
To a solution of 3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-azepan-2-one (50 mg, 0.12 mmol) in DMF (15 mL) was added 3-trifluoromethyl benzoic acid (28 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and Hunig's base (0.03 mL, 0.15 mmol). The resulting mixture was stirred for 16 h before EtOAc was added. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution (aq), and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave N-[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-3-trifluoromethyl-benzamide (70 mg). MS found: (M+H)+=578.
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:16])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:18]1[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl.[Cu]I>[O:16]=[C:9]1[N:8]([C:18]2[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)=[O:23])=[CH:20][CH:19]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10]1
Reactant: O=C1NC(c2ccccc2)C2(CCCC2)O1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccc2cccnc12)c1ccc(N2C(=O)OC3(CCCC3)C2c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 11 %

Procedure:
To a 50 mL dried round bottom flask containing a degassed solution of 4-phenyl-1-oxa-3-azaspiro[4.4]nonan-2-one (1 eq., 1.73 mmol) and 4-iodo-N-(quinolin-8-yl)benzamide (1.2 eq.) in DMF (15 mL), potassium carbonate (2.5 eq.) and trans (N,N)-dimethyl cyclohexanediamine (0.5 eq.) was added CuI (0.1 eq). The resulting mixture was stirred at 120° C. for 15 hours. Reaction progress was monitored by TLC (TLC eluent: 10% MeOH in DCM). The reaction mixture was cooled and poured into crushed ice (5 g). The solid thus obtained was filtered, washed with water (25 mL) and dissolved in DCM. The DCM solution was then washed with water (100 mL), washed brine (50 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography using silica gel and DCM as eluting solvent to yield (R+S) 4-(2-oxo-4-phenyl-1-oxa-3-azaspiro[4.4]nonan-3-yl)-N-(quinolin-8-yl)benzamide (90 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 8.94 (d, J=4 Hz, 1H), 8.65 (d, J=7.2 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.75-7.63 (m, 5H), 7.39-7.32 (m, 5H), 5.75 (s, 1H), 2.10-2.20 (m, 2H), 1.50-1.78 (s, 4H), 1.30-1.40 (m, 1H), 1.10-1.20 (m, 1H). m/z (ESI) 464.3 (M+H)+.
Reaction SMILES: CN(C)CCCN(C)C.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[C:13]([CH3:28])[N:12]=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:31]=1[S:38](Cl)(=[O:40])=[O:39].Cl>C1COCC1.O.C(#N)C>[NH2:10][C:11]1[N:16]=[C:15]([O:17][S:38]([C:31]2[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=2[CH3:29])(=[O:40])=[O:39])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[C:13]([CH3:28])[N:12]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)CCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
N,N,N′,N′-Tetramethyl-1,3-propanediamine (56.7 g) was added dropwise to a suspension of the product from step (ii) (85.0 g) and 2,4,6-trimethylbenzenesulfonyl chloride (87.8 g) in THF (452.9 g), and the mixture was heated at 45° C. for 7 hours. 2.5% HCl in water (1291 g) was added to the mixture, and the mixture was stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g), and dried to give the crude subtitle compound as a solid. A stirred suspension of the solid in acetonitrile (654.5 g) was heated at 70° C. for 30 minutes, cooled to 5° C. and stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g) and dried to give the subtitle compound as a solid, 113.1 g; 1H NMR CDCl3: δ 7.24 (d, 2H), 7.11 (d, 2H), 6.96 (s, 2H), 4.71 (s, 2H), 3.90 (s, 2H), 3.71 (s, 2H), 2.59 (s, 6H), 2.32 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:5]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1F
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an acetic anhydride (15.5 mL) was added dropwise formic acid (6.1 mL) at 0 degrees under an atmosphere of argon. The mixture was stirred at 50 degrees for 2 hours. After the reaction mixture was cooled to room temperature, it was diluted with tetrahydrofuran (THF; 10 mL). To the diluted solution was added 2-fluoroaniline (5.56 g) in THF (20 mL) at room temperature and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=O)=[CH:16][C:3]1=2.S(Cl)(Cl)=O.Cl.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>CN(C)C=O.C(Cl)Cl.O>[OH:29][CH2:28][C:27]([NH:26][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(N)CO
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 0 °C
Yield: 41.3 %

Procedure:
A water cooled stirred suspension of 13.41 g (0.05 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl acetic acid, 50 ml of sieve-dried methylene chloride and three drops of dimethylformamide was treated for a few minutes with 6.54 g (0.055 mol) of thionyl chloride. After total addition the suspension was stirred 15 minutes with cooling and was then intermittently warmed until the evolution of HCl ceased. A stirred ice water chilled solution of 13.37 g (0.15 mol) of 2-amino-2-methyl-1-propanol and 50 ml of sieve-dried methylene chloride was treated dropwise over 0.5 hour with the acid chloride solution. After total addition the resultant suspension was stirred with cooling for 20 minutes and was then stirred 1.5 hours at ambient temperature. The suspension was vacuum filtered and the filtrate was washed with 100 ml each of 5% HCl, water, and 5% Na2CO3. The organic phase was dried by extracting with 500 ml of saturated NaCl solution and then over anhydrous Na2SO4. The resultant mixture was filtered and the filtrate was concentrated to an oil which was dried by azeotropic distillation of absolute ethanol to afford 14.3 g (84.3%) of a crude product. Two recrystallizations from benzene and a final recrystallization from isopropanol afforded 7.0 g (41.2%) of crystals of 6,11-dihydro-N-(1-hydroxy-2-methyl-2-propyl)-11-oxodibenz[b,e]oxepin-2-yl acetamide, m.p. 132°-134° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[CH:10]=[C:5]2[C:4]([CH3:24])=[N:3]1.[C:25]([O:29][C@@H:30]([C:36]1[C:51]([CH3:52])=[CH:50][C:39]2[N:40]=[C:41]([C:43]3[CH:48]=[CH:47][N:46]=[C:45](Cl)[CH:44]=3)[S:42][C:38]=2[C:37]=1[C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:28])([CH3:27])[CH3:26].[Cl-].[Li+].C([SnH](CCCC)CCCC)CCC>O1CCOCC1.ClCCl.[Cu]I.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.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:25]([O:29][C@@H:30]([C:36]1[C:51]([CH3:52])=[CH:50][C:39]2[N:40]=[C:41]([C:43]3[CH:48]=[CH:47][N:46]=[C:45]([C:9]4[CH:10]=[C:5]5[C:4]([CH3:24])=[N:3][N:2]([CH3:1])[C:6]5=[CH:7][N:8]=4)[CH:44]=3)[S:42][C:38]=2[C:37]=1[C:53]1[CH:54]=[CH:55][C:56]([Cl:59])=[CH:57][CH:58]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cc5c(C)nn(C)c5cn4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine (31 mg, 0.071 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.1 mg, 0.057 mmol), copper(I) iodide (13.5 mg, 0.071 mmol) and lithium chloride (15.1 mg, 0.355 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (8.9 mg, 0.0008 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (5.2 mg, 0.007 mmol) were added and reaction mixture was heated at 120° C. for 5 hours. Reaction mixture was cooled to rt, diluted with dichloromethane, adsorbed onto silica gel and purified by CombiFlash (0 to 70% EtOAc/Hex) to give product contaminated with tributylstannane impurity. LCMS-ESI+: calc'd for C35H35ClN5O3S: 640.2 (M+H+); Found: 640.4 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Reactant: NC(CO)CO
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC(CO)CO)nc3N(C3CCCC3)C2=O)c1F
Yield: 71.4 %

Procedure:
1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.50 g (1.11 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.30 g (3.32 mmol) of serinol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.38 g (72%) of the title compound: mp 172° C.–174° C. MS (APCI) (m+1)/z 480.1.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([OH:22])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][C:2]([C:14](=[O:22])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C(O)c1ccccc1
Product: O=C(c1ccccc1)c1ccc2c(c1)Cc1cc(C(=O)c3ccccc3)ccc1-2

Procedure:
The compound 2,7-bis(dimethylphenylcarbyl) fluorene, which is believed to be a new compound, was prepared by reacting benzoic acid with fluorene in hot polyphosphoric acid at about 100° C. to yield 2,7-dibenzoylfluorene which is then reacted with trimethyl aluminum in boiling toluene.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][CH:20]1[CH2:24][CH2:23][O:22][C:21]1=[O:25]>C(OCC)(=O)C>[Si:6]([O:19][CH:20]1[CH2:24][CH2:23][O:22][C:21]1=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCCC1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.0 g of imidazole and 15.9 g of t-butyldimethylsilyl chloride were added in order to a dimethylformamide (180 ml) solution of 9.0 g of 3-hydroxydihydrofuran-2-(3H)-one, and the reaction liquid was stirred for 1 hour at room temperature. The reaction liquid was diluted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to obtain the entitled compound as a colorless oily substance.