Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N+:25]#[C-:26])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][CH:9]=1.[O:27]=[C:28]([CH3:42])/[CH:29]=[N:30]/[CH:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1>CN(C=O)C>[C:28]([C:29]1[N:30]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]2)[CH:26]=[N:25][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)(=[O:27])[CH3:42]
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)/C=N/C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (15.0 g, 108 mmol) was added to a solution of 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2, see Organic Syntheses; Wiley & Sons: New York, 2004; Collect. Vol. 10, p. 692) (12.5 g, 43.2 mmol) and tert-butyl 3-{[(1E)-2-oxopropylidene]amino}azetidine-1-carboxylate (C1) (10 g, 44 mmol) in DMF (150 mL). The mixture was stirred for 16 hours at room temperature, then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was washed with water (3×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Eluant: 1:1 petroleum ether: ethyl acetate) to give the product as a solid. Yield: 11 g, 31 mmol, 72%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>C1COCC1.O>[I:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(C(F)(F)F)ccc1I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(C(F)(F)F)ccc1I
Reaction time: 0.5 h

Procedure:
Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) in THF (300 mL) at 0° C. under N2. The reaction was heated at reflux for 90 min and then carefully quenched with 6N HCl until no further gas evolution. The reaction was diluted with H2O (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid. LCMS=285.0 (M−17)+. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, J=8.3 Hz, 1 H), 7.79 (s, 1 H), 7.28 (d, J=8.4 Hz, 1 H), 4.75 (s, 2 H). An alternative procedure is as follows: To a solution of 2-Iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A, 9 g) in THF (100 mL) and water (10 mL) at 0° C. was added NaBH4 (0.5 g). The reaction was stirred 30 minutes. To the reaction mixture was added dilute aqueous HCl (cautiously). The mixture was extracted with ether and the ether layer was washed with water, then brine. The ether layer was then dried over anhydrous MgSO4, filtered and concentrated. The material is chromatographed on SiO2 using a step gradient of 1:3 CH2Cl2/hexanes, then 1:1 CH2Cl2/hexanes, then 100% CH2Cl2 to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[CH:25][C:26]([Br:33])=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[CH:25][C:26]([Br:33])=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccc(Br)c2cccnc12
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(Br)c3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 24.8 %

Procedure:
To a stirred solution of 40 mg (0.139 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-amino-5-bromoquinoline (47 mg, 0.209 mmol) was added. The resulting mixture was stirred at room temperature for five days and heated at 50° C. during four days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 4:1) to yield the title compound (16 mg, 25% yield).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[O:35][CH3:36])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:33])[CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4OC)n3)c(OC)cc21
Yield: 72.4 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (55 mgs) and N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine (66 mgs) were converted to the title compound (78 mgs) as a white solid. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.53 (s, 1H), 6.69 (s, 1H), 6.37-6.35 (m, 2H), 4.35-3.8 (broad absorption, 2H), 3.90 (d, J=7.3 Hz, 6H) 2.98 (d, J=0.8 Hz, 3H), 2.65-2.50 (m, 1H), 2.30-2.00 (m, 3H), 1.6 (broad s, 2H), 1.15 (t, J=7.0 Hz, 3H); LC/MS: found (M+H)+=511.46 MP: 183-185° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6](=[O:7])[O:5][C@@H:4]2[CH2:8][C@@H:9]([CH3:12])[CH2:10][CH2:11][C@@H:3]12.C[C@@H]1C(=O)O[C@H]2C[C@@H](C)CC[C@@H]12.C[C@H]1C(=O)O[C@H]2C[C@@H](C)CC[C@H]12.C[C@H]1C(=O)O[C@@H]2C[C@@H](C)CC[C@@H]12>>[CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C@@H:4]2[CH2:8][C@@H:9]([CH3:12])[CH2:10][CH2:11][C@H:3]12
Reactant: C[C@H]1CC[C@H]2[C@H](C)C(=O)O[C@@H]2C1
Agent: C[C@H]1CC[C@@H]2[C@@H](C1)OC(=O)[C@@H]2C
Agent: C[C@H]1CC[C@@H]2[C@H](C1)OC(=O)[C@H]2C
Agent: C[C@H]1CC[C@H]2[C@H](C1)OC(=O)[C@@H]2C
Product: C[C@H]1CC[C@H]2[C@@H](C1)OC(=O)[C@@H]2C

Procedure:
(3S,3aS,6S,7aR)-Perhydro-3,6-dimethyl-2-benzo[b]furanone, (3S,3aS,6S,7aS) -perhydro-3,6-dimethyl-2-benzo[b]furanone, (3R,3aR,6S,7aS)-perhydro-3,6-dimethyl-2-benzo[b]furanone and (3R,3aS,6S,7aR)-perhydro-3,6-dimethyl-2-benzo[b]furanone were also prepared.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[Cl:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]2(O)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1>>[Cl:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([CH:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(F)c(Cl)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(F)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-chloro-5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 348 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[CH:7](OC)OC.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]2[C:13]=1[CH:7]=[C:6]([OH:12])[N:5]=[CH:4]2
Reactant: COC(OC)C(=O)NCc1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1cc2c(Cl)ccc(Cl)c2cn1

Procedure:
A solution of N-(2,5-dichlorobenzyl)-2,2-dimethoxyacetamide (1.0 g, 3.6 mmol) in sulfuric acid (18M; 4 mL) was stirred at 50° C. for 1 h. The reaction mixture was charged with ice and neutralized with NaHCO3. The aqueous mixture was extracted with 5% MeOH in DCM (3×), washed with NaHCO3, dried over sodium sulfate, filtered and concentrated to afford the title compound as yellow solid. MS (ES+): m/z=215.75/217.75 (3:1) [MH+]. HPLC: tR=2.76 min (ZQ2, polar—5 min).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7]
Reactant: BrCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCBr
Reaction time: 10 h

Procedure:
A mixture of phthalimide potassium salt (2 g; 10.8 mmol), 1,4-dibromobutane (10.8 g; 50 mmol) and dry dimethylformamide (10 ml) was stirred at a bath temperature of 90° to 100° C. for 10 hours. The precipitated crystals were removed by filtration, and the filtrate was concentrated under reduced pressure. Excess of 1,4-dibromobutane was removed by distillation, and the residue was purified by silica gel column chromatography to give the objective compound. M.P., 81°-82° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].B(Br)(Br)Br>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of cis chrysanthemic acid (2.0 g) in toluene (18 ml) was added a solution of boron tribromide (13 mg) in toluene (2.2 ml) at room temperature under a nitrogen atmosphere. Irradiation with a high pressure mercury lamp (100 W) was made for 10 minutes under stirring. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (1.98 g). A part of the reaction solution was converted to ethyl ester. Gas chromatography assay gave the isomer ratio of the product: cis, 6.8%; and trans, 93.2%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: FC1CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.165 g, 0.42 mmol), 1-azetidin-3-yl-4-fluoropiperidine (0.1 g, 0.63 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.179 g, 0.84 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 10:90) to give 491 as a yellow solid (0.1 g, 45%). LCMS (Method I): RT=2.52 min, [M+H]− 534.2. 1H NMR (400 MHz, DMSO-d): δ 8.03-7.99 (m, 1 H); 7.64-7.61 (m, 1 H); 7.26-7.21 (m, 2 H); 4.81-4.52 (m, 1 H); 4.51-3.96 (m, 4 H); 3.86 (s, 2 H); 3.79-3.76 (m, 7 H); 3.43 (t, J=6.3 Hz, 2 H); 3.26 (q, J=7.4 Hz, 2 H); 2.97 (t, J=6.3 Hz, 2 H); 2.95-2.91 (m, 1 H); 2.37-2.33 (m, 2 H); 2.18-2.13 (m, 2 H); 1.90-1.75 (m, 2 H); 1.76-1.64 (m, 2 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([O:3]CC)=O.O>O1CCCC1>[C:6]1([C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:3])[CH:6]2[CH2:15][CH2:14][C:13]3[NH:12][C:11](=[O:16])[N:10]4[CH:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[F:26])[N:19]=[C:9]4[C:8]=3[CH2:7]2)[CH:15]=[CH:14][CH:13]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CC(C(O)(c1ccccc1)c1ccccc1)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (110 mg) in 15 mL of anhydrous tetrahydrofuran was added 2 mL of 1.8M phenylithium. The reaction was allowed to stand for 15 minutes and then quenched with 1 mL of 10% acetic acid. The solvent was removed in vacuo and the crude reaction mixture triterated with water. The solid was then collected and dried to yield 9-(Diphenylhydroxymethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 46), m.p. 315°-318° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1NS(=O)(=O)c1ccc(OC)cc1
Yield: 96.2 %

Procedure:
To a solution of 0.139 g (0.412 mmol) of the product of Example 31 in 2.0 mL of DMF was added 0.70 g (1.03 mmol) of imidazole and 0.075 g (0.495 mmol) of t-butyldimethylsilyl chloride. The reaction mixture was then srtied at room temperature for 3h and then diluted with 75 mL of ether. The resulting mixture was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.179 g (96%) of the desired product as a white solid. Electrospray Mass Spec: 452.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[N:10]=[CH:11][NH:12][C:13](=O)[C:14]=3[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]cnc2c1nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
8,9-diphenyl-1H-purin-6(9H)-one obtained in step 3 (22.3 g, 77.4 mmol) was dissolved in POCl3 (70 ml) at 0° C. and the reaction mixture was heated to reflux at 110° C. overnight. After cooled to room temperature, ice-water was added to the resulting reaction mixture and stirred for 30 min at room temperature. The resulting mixture was filtered with water. The collected solid was dried under reduced pressure to obtain the title compound (20 g, 84%) as beige solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:21]([O:29][CH2:30][C@@H:31]1[C:35]([O:37][C:38](=[O:40])[CH3:39])([CH3:36])[C@:34]([F:42])([CH3:41])[CH:33](OC(=O)C)[O:32]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[C:21]([O:29][CH2:30][C@@H:31]1[C:35]([O:37][C:38](=[O:40])[CH3:39])([CH3:36])[C@:34]([F:42])([CH3:41])[CH:33]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])[O:32]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C(C)(OC(C)=O)[C@@]1(C)F
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)[C@]1(C)F
Yield: 61.7 %

Procedure:
To a stirred solution of uracil (about 0.30 g, 2.71 mmol) in acetonitrile (about 7 ml) was added N,O-Bis(trimethylsilyl)acetamide at room temperature (about 4 ml, 16.3 mmol) and refluxed for about 2 hours. To this added ((2R,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.5 gm, 1.35 mmol) in acetonitrile (about 8 ml) drop wise at about 0° C., and added SnCl4 (about 0.2 ml, 2.03 mmol) and refluxed for about 15 hours, Completion of the reaction monitored by thin-layer chromatography and neutralized the reaction mixture with saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 35% ethyl acetate/hexane as eluent furnished title compound (0.35 g) as a colorless solid. Yield: 61%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.67 (s, 1H), 8.06-8.03 (m, 2H), 7.59-7.33 (m, 4H), 6.39 (d, 1H, J=22.8 Hz), 5.76, 5.55 (dd, 1H, J=2.1 Hz, J=2.4 Hz), 4.80-4.43 (m, 3H), 2.13 (s, 3H), 1.81 (d, 3H, J=2.4 Hz), 1.49 (d, 3H, J=23.4 Hz); ES Mass: [M+Na] 443 (100%); IR cm−: 3433, 2931, 2346, 1713, 1385, 1274, 952, 712; HPLC: 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:17])[N:12]([CH2:14][CH2:15][O:16][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=c1ccc(-c2cccc(F)c2)cn1CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(-c4cccc(F)c4)ccc3=O)ccnc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
The crude 5-(3-fluorophenyl)-1-(2-hydroxyethyl)pyridin-2(1H)-one, 4-chloro-7-methoxyquinoline (107 mg, 553 μmol), cesium carbonate (191.2 mg, 587 μmol), palladium(II) acetate (24.6 mg, 110 μmol), and racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (50.2 mg, 126 μmol) were suspended in a microwave vial in toluene (3.0 ml) and sealed under argon. The tube was heated in a preheated oil bath (70° C.) and stirred for about 2 hours. The reaction was then cooled to room temperature and filtered through a silica gel filter [5:1 CH2Cl2/(2 N ammonia in MeOH)]. The filtrate was concentrated and purified on reverse phase HPLC (10%->95% MeCN/water with 0.1% TFA over 40 minutes on Shimatzu HPLC). The fractions with product were collected, concentrated, washed with Et2O, and then purified on a silica gel column (25:1->10:1 CH2Cl2/MeOH->10:1 CH2Cl2/2 N ammonia in MeOH) to afford the desired product (22.8 mg, 58.4 μmol, 13% yield over two steps). MS (ESI pos. ion) m/z (MH+): 391. Calc'd exact mass for C23H19FN2O3: 390. 1H NMR (400 MHz, CDCl3): 8.67 (d, J=5.0 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.61 (dd, J=9.0 Hz, 2.0 Hz, 1H), 7.40-7.36 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 3H), 6.70 (d, J=9.0 Hz, 1H), 6.67 (d, J=5.2 Hz, 1H), 4.62-4.54 (m, 4H), 3.94 (s, 3H).
Reaction SMILES: [CH:1]1([Zr:6](C)C)[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1>C1(C)C=CC=CC=1>[CH:1]1([Zr:6]([O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:18])[F:19])[CH:12]=2)[O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:12]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: C[Zr](C)C1C=CC=C1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(O[Zr](Oc2cccc(C(F)(F)F)c2)C2C=CC=C2)c1
Temperature: 25 °C

Procedure:
To a 50 ml Schlenk flask containing 138.7 mg (0.5 mmole) of (1-methylboratabenzene) (cyclopentadienyl) dimethyl zirconium [intermediate product of 1st Step] in 15 ml toluene and at 0° C., 162.1 mg (1 mmole) of Trifluoro-m-Cresol in 10 ml toluene is added slowly under stirring. After warming up to room temperature and stirring one hour at room temperature, toluene of the reaction mixture is moved by vacuum. The desired product (1-methylboratabenzene) (cyclopentadienyl) bis(3-trifluoromethylphenoxy) zirconium can be obtained from the residue of vacuum distillation.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].B.C1COCC1>>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: B
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc([C@@H](O)CBr)cc1

Procedure:
The title compound was prepared from N-[4-(2-bromoacetyl)phenyl]methanesulfonamide (0.23 g, 0.82 mmol) (which was obtained in Example 111), and 1M BH3/THF solution (10.35 mL, 10.5 mmol) in substantially the same manner, as described in Example 103 and was obtained as a white solid (1.75 g, 72% yield); MS (ES) m/z: 293 (M)+; 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, 2H), 2.95 (s, 3H), 3.53 (m, 1H), 3.55 (m, 1H), 4.73 (m, 1H), 5.75 (d, 1H), 7.14 (d, 2H), 9.74 (s, 1H).
Reaction SMILES: [N:1]1([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1>Cl>[N:1]1([CH2:10][C:11]([OH:13])=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Cn1ncc2ncccc21
Agent: Cl
Product: O=C(O)Cn1ncc2ncccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Tert-butyl 1H-pyrazolo[4,3,b]pyridin-1-ylacetate (Preparation 189, 220 mg, 0.944 mmol) was dissolved in HCl (4 mL, 4.0 M in 1,4 dioxane) and stirred under nitrogen at room temperature for 4 hours. The mixture was evaporated in vacuo and the residue was triturated with anhydrous diethyl ether to afford the title compound as an off white solid in 60% yield, 120 mg.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[CH3:15][C:16]([S@:19]([NH:21][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1)[CH3:11])=[O:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)cc1
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (0.35 g, colorless oil) from 1-(4-(trifluoromethoxy)phenyl)ethanone (0.30 g, 1.47 mmol) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH2:15])[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:8]=1
Reactant: CN(C)CCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCC(N)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
Hydrogen chloride (4M in dioxane, 1.132 mL, 32.61 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamate (Intermediate 32) (0.051 g, 0.16 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 4 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-N3,N3-dimethylpropane-1,3-diamine (0.032 g, 92%) as a colourless oil.