Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]1([CH:13]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][N:21]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH:1]1([C:4]([N:18]2[CH2:19][CH2:20][C:15]3([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[CH:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:14]3)[CH2:16][CH2:17]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(C1CC1)N1CCC2(CC1)OC(c1ccccc1)C1CCCCN12
Reaction time: 8 h

Procedure:
The hexahydro-1'-(cyclopropylcarbonyl)-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-pipridine] used as the starting material in the above procedure can be prepared by the following procedure. Cyclopropanecarboxylic acid chloride, 2 g, is added dropwise to a stirred solution of 4 g of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] and 2.8 ml of triethylamine in 100 ml of methylene dichloride at 50° C. the reaction mixture is allowed to stand at room temperature overnight and then stirred with 75 ml of water. The organic layer is separated, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness. The residual oil is crystallized from 30 ml of cyclohexane to obtain 4.2 g of hexahydro-1'-(cyclopropylcarbonyl)-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 110°-114° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([O:14]CC)=[O:13])=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]1COC[CH2:30]1.CO>CCOCC>[CH2:29]([CH:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([F:1])=[CH:3][C:4]=1[C:17]#[CH:18])[C:12]([OH:14])=[O:13])[CH3:30]
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1cc(F)c([N+](=O)[O-])cc1C(CC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.85 g, 2.6 mmol) and K2CO3 (3.6 g) were dissolved in THF/MeOH (5:1, 30 mL) and the mixture was stirred overnight at RT. The reaction mixture was diluted with Et2O and washed with sat'd NH4Cl solution. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain ethyl 2-(2-ethynyl-4-fluoro-5-nitrophenyl)acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.C(OC=[CH:19][C:20](=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.[C:28](O)(=O)C>>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:19])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC=CC(=O)CC(=O)OCC
Reactant: CC(=O)O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Product: CCOC(=O)c1cnc2nc(SCc3ccccc3)nn2c1C
Yield: 33 %

Procedure:
A solution of 15 g (73 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 15.0 g (80.0 mmol) of ethyl ethoxymethyleneacetoacetate in 250 ml of glacial acetic acid was heated at reflux for 60 hours. After cooling the volume of the reaction was reduced to approximately one quarter of the oroginal volume by evaporation at reduced pressure. The resulting residue was poured into water, and the solid which separated was collected by filtration, washed with water and dried to yield 7.88 g (33%) of the desired product as a solid, m.p. 98°-99° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[O-:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li+].CC([N:28](C)C)=O>O>[NH2:28][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:19][CH:20]=1
Reactant: [O-]c1ccccc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: CC(=O)N(C)C
Agent: [Li+]
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (80 mg, 0.35 mmol), and lithium phenoxide (1 mL, 1.04 mmol, 1M solution in THF) were suspended in DMAC (2 mL), and stirred for 4 h at 100° C. The reaction mixture was cooled to room temperature, and diluted with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 137 (22 mg, 22% yield) as a tan solid. LC-MS (M+H=289, obsd.=289). 1H NMR (400 MHz, d6-DMSO): δ 12.12 (s, 1H), 9.08 (d, 1H), 8.42 (dd, 1H), 8.28 (d, 1H), 7.88 (td, 1H), 7.70 (t, 1H), 7.55 (m, 2H), 7.35 (m, 3H), 6.55 (d, 1H).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[C:7]([CH3:36])=[C:8]([C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19]CC2C=CC=CC=2)[CH:11]=1.[H][H]>[Pd].O1CCOCC1>[CH3:4][O:5][C:6]1[C:7]([CH3:36])=[C:8]([C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([OH:19])[CH:11]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(O)c2)c(OC)c(OC)c1OC
Yield: 75.4 %

Procedure:
10% Pd—C (50 mg) was added to an ethanol (10 ml) and dioxane (10 ml) mixed solution of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (150 mg, 0.3554 mmol) and the resulting solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with hexane to obtain the titled compound (97 mg, 0.2679 mmol, 75%).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:19]([CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:35][CH:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride (4.58 mmole) in ether (5 ml) is added to a ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmole) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×2 mm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band with Rf=0.55 is extracted with ether and evaporated to give the desired ester (0.85 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[C:12]1([CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8](=[O:10])[CH3:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Cc1ccncc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccccc1)c1ccncc1
Yield: 78.7 %

Procedure:
Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78%) was obtained as a crystalline solid: m. p. 101-103° C. Anal. Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Reaction SMILES: FC(F)(F)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:19][C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[C:22]([F:32])[C:21]=2[F:33])C(=O)C(F)(F)F)=[CH:8][C:7]=1[C:34](=[O:36])[NH2:35])=O>CO.O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:19][C:20]2[C:21]([F:33])=[C:22]([F:32])[C:23]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:27])[C:25]=2[F:26])=[CH:8][C:7]=1[C:34]([NH2:35])=[O:36]
Reactant: NC(=O)c1cc(N(Cc2c(F)c(F)c(C(F)(F)F)c(F)c2F)C(=O)C(F)(F)F)ccc1OC(=O)C(F)(F)F
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of 2-carbamoyl-4-[2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl-(2,2,2-trifluoroacetyl)amino]phenyl trifluoroacetate (300 mg, 0.52 mmole) in methanol (8 ml) and water (3 ml) was added c-HCl (2.0 ml) at 40° C. under a nitrogen atmosphere. After the reaction mixture was stirred for 24 hr, the organic solvent was removed in vacuo. The residue was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water and then dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was recrystallized from methylene chloride/hexane (1:10) to give 120 mg (60% yield) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide as a white solid.
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:14])[CH2:4][CH:5]2[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH2:15]([SH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.[Cl-].[NH4+]>CO>[CH2:15]([S:22][C:2]1[C:3](=[O:14])[CH2:4][CH:5]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CC(OC2CCCCO2)C2OC12
Reactant: CCCCCCCS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCSC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
2,3-Epoxy-4-tetrahydropyranyloxycyclopentan-1-one (200 mg) and 121 mg of n-heptylmercaptan were dissolved in 5 ml of methanol, and 158 mg of triethylamine was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was treated by a customary procedure to afford 280 mg of a crude product. The crude product was chromatographed on a thin layer plate with cyclohexane/ethyl acetate (=6/4) to afford 80 mg of 2-n-heptylthio-4-tetrahydropyranyloxycyclopent-2-en-1-one in a yield of 26%. The product had the following characteristics.
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:18])[N:5]([CH3:17])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[C:19](OC)([O:23]C)([O:21][CH3:22])[CH3:20].C(O)(=O)C(C)(C)C>COCCOCCOC>[CH3:22][O:21][C:19]([CH2:20][C:8]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH3:17])[C:4](=[O:18])[C:3]1=[CH2:2])=[O:23]
Reactant: COc1cccc(C2=C(CO)C(=O)N(C)CC2)c1
Reactant: COC(C)(OC)OC
Agent: CC(C)(C)C(=O)O
Solvent: COCCOCCOC
Product: C=C1C(=O)N(C)CCC1(CC(=O)OC)c1cccc(OC)c1

Procedure:
The allylic alcohol 27 of Example 9 (1.22 g, 4.96 mmol), trimethyl orthoacetate (5.52 g, 46 mmol), and pivalic acid (25 mg, 0.50 mmol) were placed in diglyme (25 mL) and refluxed at 155°-160° C. (internal) with fractionation to remove CH3OH. after 18 h the solvents were evaporated and the residue distilled [bp 175°-185° C. (0.15 mm)] to return 1.21 g (80%) of methyl ester 28. Upon standing the ester crystallized: mp 85°-86° C.; NMR δ7.30 (m, 1H), 6.86 (m, 4H), 6.65 (s, 1H), 5.57 (s, 1H), 3.76 (s, 3H), 3.47 (s 3H), 3.17 (m, 3H), 2.87 (s, 4H), 2.53 (m, 2H); IR 1733, 1653, 1595 cm-1 ; mass spectrum m/e (rel intensity) 303 (38), 230 (100). Anal. Calcd for C17H21NO4 : C, 67.3; H, 7.0; N, 4.6. Found: C, 67.2; H, 7.0; N, 4.6.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10](O)([C:11]3[CH:12]=[CH:13][C:14]([Cl:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=3)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[SH:23][CH2:24][CH:25]([CH3:36])[C:26]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31])=[O:27].Cl>C(OCC)(=O)C>[NH2:20][S:17]([C:15]1[CH:16]=[C:11]([C:10]2([S:23][CH2:24][CH:25]([CH3:36])[C:26]([N:28]3[CH2:35][CH2:34][CH2:33][C@H:29]3[C:30]([OH:32])=[O:31])=[O:27])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[NH:9]2)[CH:12]=[CH:13][C:14]=1[Cl:21])(=[O:19])=[O:18]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NS(=O)(=O)c1cc(C2(O)NC(=O)c3ccccc32)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(CSC1(c2ccc(Cl)c(S(N)(=O)=O)c2)NC(=O)c2ccccc21)C(=O)N1CCC[C@H]1C(=O)O
Yield: 48.4 %

Procedure:
A mixture of 1.69 g chlorthalidone, 2.5 g of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 150 ml ethyl acetate is cooled by an ice bath and then saturated with HCl gas. This mixture is refluxed for one hour. The solvent is evaporated, the residue dissolved in warm saturated sodium bicarbonate solution, and the mixture extracted with ethyl acetate. The aqueous phase is separated and acidified at ice bath temperature. The resulting solid is filtered off, washed with water and dried to yield 1.3 g of the title compound.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCN(CC)CC.CC(C)(C)C(Cl)=O.[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1.[Li+].[Cl-]>C1COCC1>[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[N:24]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirred solution of valeric acid (3.83 mL, 35.2 mmol) and Et3N (14.7 mL, 106 mmol) in dry THF (175 mL) was added trimethylacetyl chloride (5.29 mL, 42.3 mmol) dropwise. The mixture was stirred at 0° C. for 1 hour and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (7.50 g, 42.3 mmol) was added followed by LiCl (1.79 g, 42.3 mmol). The reaction was warmed to room temperature overnight with good stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. Et2O (75 mL) was added to the residue, which was washed with sat. NaHCO3 (3×40 mL), 1N HCl (3×40 mL), and brine (2×40 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:20]([O:21][CH3:22])[CH3:19])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(4′-Bromobiphenyl-4-yl)acetic acid (12 g, 37 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and methanol (200 mL), and N,O-dimethylhydroxylamine hydrochloride (5.4 g, 56 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (15 g, 60 mmol) and N-methylmorpholine (6.1 mL, 56 mmol) were added, followed by stirring at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.45 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (12 g, 37 mmol) as a white solid (yield 100%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1(O)[CH2:7][O:6][C:5]([CH:8]([CH3:10])[CH3:9])=[N:4]1.O=S(Cl)Cl>ClCCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1
Reactant: CC(C)C1=NC(O)(CCl)CO1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)c1nc(CCl)co1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A solution of 4-chloromethyl-4-hydroxy-2-isopropyloxazoline (4.88 g, 0.0275 mol) in 1,2-dichloroethane (20 mL) was added to a solution of SOCl2 (2.40 mL, 0.0329 mol) in 1,2-dichloroethane (80 mL) at 0° C. under argon, and the solution was heated to 70° C. After 15 min at 70° C., the reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Drying the residue on high vacuum gave the desired compound as a brown semi-solid (4.20 g, 0.0263 mol, 96%): 1H NMR (CDCl3) δ1.36 (d, J=7.5 Hz, 6H), 3.03-3.18 (m, 1H), 4.50 (s, 2H), 7.56 (s, 1H). Mass spectrum: (M+H)+ =160, 162.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5](=[O:7])[N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[N:3]1[CH2:18][C:19]#[CH:20].[BH4-].[Na+].OS(O)(=O)=O>C1COCC1.CCO>[OH:7][CH:5]1[N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[N:3]([CH2:18][C:19]#[CH:20])[C:2]([CH3:21])([CH3:1])[CH2:6]1
Reactant: C#CCN1N(C(=O)OCc2ccccc2)C(=O)CC1(C)C
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C#CCN1N(C(=O)OCc2ccccc2)C(O)CC1(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
To a stirred solution of 104 (3.0 g, 10.48 mmol) in THF (75 mL) and EtOH (50 mL), sodium borohydride (2.6 g, 68.1 mmol) was added at −20° C. followed by few drops of conc. H2SO4 and stirred for 3 h at −20° C. The reaction mixture was quenched with sat. NaHCO3 solution at −20° C. and allowed to reach room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to get crude compound which was purified through silica gel column chromatography, eluted with 15% EtOAc/hexanes to get 105 (2.3 g, 76%). 1H NMR (CDCl3) δ 7.26-7.37 (m, 5H), 5.76 (m, 1H), 5.25 (s, 2H), 3.80-3.60 (m, 3H), 2.48-2.38 (m, 1H), 2.22 (m, 2H), 1.38 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH3:21])[C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:20])=[O:9])=[CH:4][CH:3]=1.C([O:26][CH:27]=[C:28]([C:34](OCC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[CH2:32]([O:31][C:29]([CH:28]1[C:27](=[O:26])[C:15]2[C:14](=[C:13]3[C:18](=[CH:17][CH:16]=2)[CH:19]=[C:10]([C:8](=[O:9])[N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:21])[CH:11]=[N:12]3)[N:20]=[CH:34]1)=[O:30])[CH3:33]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN(Cc1ccc(F)cc1)C(=O)c1cnc2c(N)cccc2c1
Product: CCOC(=O)C1C=Nc2c(ccc3cc(C(=O)N(C)Cc4ccc(F)cc4)cnc23)C1=O
Yield: 64 %

Procedure:
Using a procedure analogous to that described in Example 2 in the section relating to the preparation of starting materials 3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-8-aminoquinoline was reacted with diethyl ethoxymethylenemalonate to give 3-ethoxycarbonyl-8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 64% yield, mp 206-207° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CS(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:35]([C@@H:47]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:48][CH2:49][N:50]([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])[CH:34]=1)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[NH3:7].[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([C@@H:47]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH2:48][CH2:49][N:50]([CH:54]([CH3:55])[CH3:56])[CH:51]([CH3:52])[CH3:53])[CH:34]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOS(C)(=O)=O)ccc1OCc1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 120 °C
Reaction time: 8 h

Procedure:
tert-butyl[2-(4-hydroxyphenyl)ethyl]carbamate (Prepared according to WO1998/43942, 3.8 g, 7.3 mmol), potassium carbonate (2.6 g, 8.0 mmol), potassium iodide (1.1 g, 7.3 mmol) and 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethyl methanesulfonate (preparation 36, 1.56 g, 2.98 mmol) were stirred in toluene (20 ml) and stirred at 120° C. overnight. After cooling, water (80 ml) and ethyl acetate (80 ml) were added, organics separated and washed with saturated aqueous sodium hydrogen carbonate (40 ml), brine (40 ml) then dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (99/1/0.1 to 90/10/1.0 by volume) to furnish the title compound as an oil, 3.4 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(=O)(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.10 g, 0.26 mmol) in THF (5 ml) at room temperature was added 1.1 equivalent of trifluoromethylsulfonyl chloride loaded TFP resin, and DMAP (0.031 g, 0.26 mmol). The reaction was then stirred at room temperature for 15 hours and filtered. The remaining resin was then washed with THF (2×10 ml for 20 min), and then combined organic fractions were concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.02 g, 15%). 1H NMR (400 MHz, CD3OD) δ7.40-7.37 (m, 2H), 7.17 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.90-5.60 (br s, 1H), 5.14-5.12 (m, 1H), 4.28-4.25 (m, 2H), 1.88-1.84 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS: Calcd.: 516. Found: [M+H]+ 517.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1F.[Br:18]C1C=CC=C(Br)C=1>>[Br:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cc1ccc(F)c(F)c1)c1ccccc1
Reactant: Brc1cccc(Br)c1
Product: O=C(Cc1ccccc1)c1cccc(Br)c1
Yield: 47.7 %

Procedure:
Followed the procedure described in Intermediate 12, starting from 1,3-dibromobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to give the desired 1-(3-bromophenyl)-2-phenylethanone (520 mg, yield 47.7%).