Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=O>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:13]/[C:12]/2=[N:7]\[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 51.4 %

Procedure:
The compound of 2-methylpropane-2-sulfinamide (29.54 g, 244.2 mmol) was added the solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (78.97 g, 268.6 mmol) in dry THF (900 mL), and then tetraisopropoxytitanium (193.1 g, 488.3 mmol) was added, The reaction mixture was reflux overnight. The mixture was removed in vacuo, and then quenched by brine, extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na2SO4, filtered, and evaporated to give (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfinamide (50 g, 40%). 1H NMR (CDCl3): 1.30 (s, 10H), 1.51 (m, 5H), 1.62 (m, 4H), 1.83 (d, 2H), 3.07(d, 1H), 3.43 (d, 1H), 5.29 (s, 2H), 6.79 (d, 1H), 7.41 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=O)=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([N:37]3[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]3)=[O:36])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)O)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)N3CC[C@H](O)C3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}phenyl)acetic acid (150 mg, 0.31 mmol), (S)-3-pyrrolidinol (54 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 71 mg, 0.37 mmol), 1-hydroxybenzotrazole hydrate (HOBT, 50 mg, 0.37 mmol), and triethylamine (0.09 mL, 0.62 mmol) in THF/CH2Cl2 (1/1, 6 mL) was stirred at room temperature overnight. The mixture was evaporated at reduced pressure, and the residue was dissolved in CH2Cl2/MeOH and purified by MPLC (EtOAc/Hexane/MeOH). 1H-NMR (DMSO-d6) δ 9.13 (s, 1H), 8.04 (m, 3H), 7.50-7.34 (m, 6H), 7.07 (d, J=8.9 Hz, 2H), 6.85 (dd, JJ=1.8 Hz, 4.8 Hz, 2H), 6.35 (s, 1H), 4.97 (dd, JJ=3.8 Hz, 44.1 Hz, 1H), 4.27 (broad d, J=30.7 Hz, 1H), 3.70-3.56 (m, 4H), 3.44-3.27 (m, 2H), 1.95-1.73 (m, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=555.2, RT=2.28 min.
Reaction SMILES: [Cl-].[CH:2]([N+](=C)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[N:14]=[CH:13][N:12]=1>C(#N)C>[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH:18]=[CH2:2])[N:14]=[CH:13][N:12]=1
Reactant: C=[N+](C(C)C)C(C)C
Reactant: Cc1ncnc(Cl)c1F
Agent: [Cl-]
Solvent: CC#N
Product: C=Cc1ncnc(Cl)c1F
Temperature: 25 °C

Procedure:
To a solution of N-isopropyl-N-methylenepropan-2-aminium chloride (13.3 g, 88.7 mmol) in acetonitrile (55 mL) was added 4-chloro-5-fluoro-6-methylpyrimidine (10.0 g, 68.2 mmol). The reaction flask was flushed with argon and the mixture was heated at reflux for 24 hours with stirring, then cooled to room temperature. Water (130 mL) was added and the mixture was extracted with dichloromethane (140 mL). The organic phase was washed with 10% aqueous KHSO4 (400 mL) and dried over Na2SO4. The solution was filtered and evaporated in vacuo at 300 millibar pressure and 35° C. tert-Butylcatechol (30 mg, 0.2 wt %, based on the mass of the crude material) was added. Residual solvent was removed under vacuum at 50° C. and the crude product was then distilled at 5 millibar pressure and 50° C. (oil bath). tert-Butylcatechol (0.1 wt %) was added to the distilled 4-chloro-5-fluoro-6-vinyl pyrimidine (7.9 g, 73%) which was obtained as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCCC1.O>CC(O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A suspension of 6-chlorooxindole (1.68 g, 10 mmol) (Cresent Chem.), 1-BOC-4-piperidone (2.20 g, 11.0 mmol) (Fluka), and piperidine (85 mg, 1 mmol) (Aldrich) in 2-propanol (30 mL) was heated at 100° C. for 2 days. Hot water (30 mL) was added to the hot reaction mixture and mixture allowed to cool to room temperature. After standing in refrigerator for 2 hours, crystalline material was collected and washed with cold aqueous methanol to give 4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-piperidine-1-carboxylic acid tert-butyl ester as a yellow crystalline material. (Yield 2.88 g, 82.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[N+:5]([O-])=[CH:6][C:7]=1[Br:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:14].CO.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([CH2:10][OH:14])[CH:3]=1
Reactant: Cc1cc(Cl)c(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: OCc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 4-chloro-5-bromo-2-picoline-N-oxide (23.9 g) in dichloromethane (250 ml) was cooled to 10° and trifluoroacetic anhydride (25 ml) added over 20 minutes. The mixture was allowed to warm to ambient temperature, and stand for 7 days. After cooling to 10°, methanol (100 ml) was added, and the solution stripped. The residue was treated with water (150 ml), basified with saturated aqueous sodium carbonate to pH 10, and extracted with ethyl acetate (2×150 ml). The combined extracts were dried (MgSO4). stripped, and triturated with ether to give 4-chloro-5-bromo-2-hydroxymethylpyridine, 16.58 g. m.p. 109°-10°.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH:15]([N:30]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[N:31]1)[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[OH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:29][CH2:14][CH:15]([N:30]3[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[N:31]3)[CH2:16][C:17]2=1
Reactant: COc1ccc2ncc(O)c(CC(CO)n3cc([N+](=O)[O-])cn3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2c1)CC(n1cc([N+](=O)[O-])cn1)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
Diethyl azodicarboxylate (250 μL, 1.87 mmol, 6.43 eq) is added at room temperature to a stirred solution of 4-[3-hydroxy-2-(4-nitro-pyrazol-1-yl)-propyl]-6-methoxy-quinolin-3-ol (100 mg, 0.29 mmol, 1.0 eq) and triphenylphosphine (122 mg, 0.46 mmol, 1.6 eq) in N,N-dimethylformamide (38 mL). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford 6-methoxy-3-(4-nitro-pyrazol-1-yl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene as a light yellow solid (60 mg, 63% yield).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: BrC1=C(Br)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(Br)CCC2)cc1
Yield: 32.6 %

Procedure:
Under nitrogen, 36.4 g (161 mmol) of 1,2-dibromocyclopentene (Aldrich) was reacted with 18.0 g (107 mmol) of 4-methylthiophenylboronic acid (Step 1) in 550 mL of toluene, 365 mL of ethanol, and 235 mL of 2M Na2CO3 in the presence of 6.0 g (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 9.39 g (22%) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (38 in Synthetic Scheme X when R5 =SCH3 and R1, R2, R3, R4, R6, and R7 =H) as a solid: mp 52°-54° C.; NMR (CDCl3) δ 1.98-2.09 (m, 2H), 2.50 (s, 3H), 2.70-2.78 (m, 2H), 2.80-2.89 (m, 2H), 7.24 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:19][CH2:18][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: NS(=O)(=O)c1ccc2ccc(O)cc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc2ccc(S(N)(=O)=O)cc2c1
Yield: 48 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 17, 7-hydroxynaphthalene-2-sulfonamide (40 mg, 0.18 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (43 mg, 0.18 mmol) were converted to the title compound (33 mg, 48%) after purification using flash column chromatography (gradient from 0% to 2% MeOH/CH2Cl2). 1H NMR (CDCl3) δ 8.31 (s, 1H), 7.84-7.82 (m, 1H), 7.77-7.73 (m, 2H), 7.26 (dd, J=8.9, 2.5 Hz, 1H), 7.19 (d, J=2.2 Hz, 1H), 4.13 (t, J=4.9 Hz, 2H), 4.02 (t, J=4.9 Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H); MS(ESI−) m/z 380.4 (M−H)−.
Reaction SMILES: [I-].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C[N+](C)(C)Cc1cccn1-c1ccccc1
Agent: Cl
Agent: [I-]
Solvent: CCOCC
Solvent: CCO
Product: c1ccc(-n2cccc2Cn2ccnc2)cc1

Procedure:
A solution of [1-phenyl-pyrrol-2-yl]methyl trimethylammonium iodide (J.A.C.S., 73, 4921, (1951) (3.42 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 7 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. Addition of an excess of ethereal hydrogen chloride gave a precipitate which was filtered off and crystallised from methanol/ethyl acetate to give 1-phenyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride (0.65 g), m.p. 140°-141°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11](O)(=[O:13])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:1][C:2]1[CH:7]=[C:6]([O:13][CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC(=O)O
Solvent: O
Product: COc1ccc(N)c(Cl)c1
Product: Nc1ccccc1Cl
Yield: 65.5 %

Procedure:
The same catalytic reduction reaction as in Example 1 was carried out except that 157.6 g (1.0 mole) of o-chloronitrobenzene was used instead of 137.1 g (1.0 mole) of o-nitrotoluene and a 50% aqueous solution of acetic acid was used instead of distilled water. The reaction required a period of 480 minutes with the absorption of 53.0 liters of hydrogen until its termination. Subsequently, the reaction solution was worked up in the same way as in Example 1 to give 8.5 g of o-chloroaniline as an initial distillate and 103.7 g (yield 65.5%) of 2-chloro-4-methoxyaniline (boiling point 141° to 143° C./20 mmHg) as a main distillate. The main distillate was found to have a purity of 99.5% by gas chromatography.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC[N:28](CC)CC.N[C:34]1[C:39]([C:40]([NH2:42])=[O:41])=[CH:38][N:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([NH:28][C:36]3[CH:35]=[CH:34][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][N:37]=3)=[O:22])[CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2O1
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cnccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C(N)=O)cn3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (15a) (77 mg, 0.21 mmol) in DMF (3 mL) was added Et3N (90.0 uL, 0.65 mmol), 4-aminonicotinic amide (60.0 mg, 0.44 mmol) and HATU (250 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 hr. The mixture was quenched with H2O (10 mL), extracted with EtOAc (2×10 mL). The organic layers was washed with H2O (2×20 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 15-30% EtOAc in hexanes to give colorless oil (39 mg, 38% yield). 1H NMR (400 MHz, CDCl3) δ 8.74 (dd, J=4.42, 1.39 Hz, 1 H) 8.46 (dd, J=8.34, 1.26 Hz, 1 H) 7.96 (d, J=8.84 Hz, 2 H) 7.52 (s, 1 H) 7.42-7.50 (m, 2 H) 7.15 (d, J=8.84 Hz, 2 H) 3.08 (s, 3 H) 2.99 (s, 2 H) 1.54 (s, 6 H); LCMS for C24H23N3O6S m/z 482.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:18][C:10]([F:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][C:5]1[C:4]([F:20])=[C:3]([CH2:21][CH2:22][OH:23])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution N-[4-chloro-2-fluor-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.05 g, 3.06 mmol), as prepared according to the procedure in the preceding step, in THF (12 mL) at 0° C. under argon was added a solution of borane-THF complex in THF (12.3 mL, 12.3 mmol, 1.0 M) over a period of 10 minutes, and the reaction mixture continued to stir until the ice-bath expired. The reaction mixture was heated at reflux for 20 hours, and allowed to cool to room temperature. A solution of K2CO3 (1.7 g, 12 mmol) in H2O (12 mL) was added, the THF was removed in vacuo, and the mixture was extracted with DCM (3 times). The extracts were combined, washed with brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAC/DCM (0 and 2.5%) to give the title compound (815 mg, 81% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.52-7.43 (m, 5H), 6.97 (dd, J=8.8, 1.7 Hz, 1H), 6.51 (t, J=8.9 Hz, 1H), 4.17 (bs, 1H), 3.83 (t, J=6.9 Hz, 2H), 3.74 (dt, J=13.4, 6.6 Hz, 2H), 3.04 (dt, J=6.9, 2.4 Hz, 2H), 1.43 (s, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H16ClF3NO (M+H): 330.1. Found: 330.3.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25].O>O1CCCC1.C(OCC)(=O)C>[NH:24]([C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:25][C:1]([O:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (1.620 g, 9.989 mmol) in anhydrous tetrahydrofuran (20 ml) was added 2-(4-hydroxyphenyl)ethanol (1.383 g, 10.01 mmol), and the mixture was stirred at room temperature for 3 hr. tert-Butyl carbazate (1.323 g, 10.01 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 40 g, ethyl acetate:hexane=4:6→5:5). The fractions containing the object product were concentrated under reduced pressure, and the obtained solid was suspended in diisopropyl ether (50 ml) and filtered. The filtered product was washed 3 times with diisopropyl ether and dried under reduced pressure to give tert-butyl 2-(4-hydroxyphenyl)ethyl hydrazine-1,2-dicarboxylate (616.7 mg, 2.08 mmol, yield 20.8%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14](Cl)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:12]=2[C:11](=[O:26])[N:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:38])([F:39])[F:29])[CH:32]=3)[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[C:12]=2[C:11](=[O:26])[N:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Oc3cccc(C(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of 3-benzyl-8-chloro-7-(4-chlorobenzyl)-1-methyl-1H-purine-2,6(3H,7H)-dione (60 mg, 0.145 mmol) in DMF (3 mL) was added 3-(trifluoromethyl)phenol (35 mg, 0.215 mmol) followed by potassium carbonate (40 mg, 0.29 mmol). The mixture was stirred at 100° C. for 2 h. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The give crude product was purified by preparative HPLC to give 3-benzyl-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (31 mg, 41.7% yield) as white solid. 1H-NMR (CDCl3) δ 7.65(s, 1H), 7.58-7.57(m, 2H), 7.45-7.41(m, 5H), 7.33-7.27(m, 5H), 5.42(s, 2H), 5.09(s, 2H), 3.41(s, 3H). LCMS retention time 3.649 min; LCMS (M+H) 541.
Reaction SMILES: BrCCC[CH2:5][C:6]([CH3:21])([C:15]1C=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:6]([CH3:21])([CH3:5])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(C)(CO)CCCCCBr
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=93), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272, found: 307.1245.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.C([Li])CCC.[F:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[C:29](N(OC)C)=[O:30]>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])[CH:6]=[CH:5]3)=[O:30])[CH:35]=[CH:36][CH:37]=1
Reactant: CON(C)C(=O)c1cccc(F)c1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc2cc(C(=O)c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) was treated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at −78° C. The solution was mixed for 15 min, and treated with a solution of 3-fluoro-N-methoxy-N-methylbenzamide (2.0 mmol) in THF (5.0 mL) at −78° C. The mixture was allowed to warm to room temperature overnight, quenched by 1 mL ethanol, concentrated, and diluted with ethyl acetate. The mixture was washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with HCl in IPA:ethyl acetate to give the dihydrochloride salt. mp 162-164° C. (dec.); MS (ESI) 363 (M+H)+; 1H NMR (DMSO-d6) δ 8.79 (1H, d), 8.53 (1H, d), 8.30 (1H, d), 8.21 (1H, dd), 7.82 (1H, d), 7.6 (4H, m), 3.9 (1H, br, m), 3.63 (2H, br, m), 3.50 (2H, br, m), 3.21 (1H, br, m), 2.2 (1H, m), 1.98 (2H, br, m), 1.7 (1H, br, m), 1.46 (1H, m), 1.30 (3H, d).