Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([CH2:21][CH3:22])[C:15]=3C(OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>Cl.O1CCCC1>[CH2:21]([C:14]1[CH:15]=[C:9]2[C:8]3[CH:4]([CH2:3][CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:5][CH2:6][C:7]=3[CH:12]=[CH:11][N:10]2[N:13]=1)[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(CC)nn2ccc3c(c12)C(CCN)CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc2c3c(ccn2n1)CCC3CCNC(C)=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
A mixture of ethyl 9-(2-aminoethyl)-2-ethyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (81.0 mg, 0.269 mmol) in 12M hydrochloric acid (3 mL) was stirred at 100° C. for 3 days, and the mixture was concentrated under reduced pressure. To a mixture of the residue and triethylamine (375 μL, 2.69 mmol) in tetrahydrofuran (2.7 mL) was added acetic anhydride (76.3 μL, 0.807 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (62.9 mg, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[F:86][C:80]1[CH:81]=[CH:82][CH:83]=[C:84]([F:85])[C:79]=1[C:77]1[S:78][C:74]([NH:73][C:71](=[O:72])[O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[C:75]([C:87](=[O:88])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:23])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([O:14][CH3:15])[CH2:12][CH2:13]2)[N:76]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COC1CCN(c2c(N)cnn2C)CCC1NC(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of Intermediate 54, N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)-2,2,2-trifluoroacetamide (150 mg, 0.45 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (580 mg, 1.12 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (159 mg, 0.45 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-methoxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (260 mg, 0.39 mmol) which was stirred with HCl in 1,4-dioxane (4 M, 4.8 mL, 19.3 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvent was removed under reduced pressure and the resulting solid was dissolved in MeOH/water (10 mL/10 mL) and to this was added K2CO3 (267 mg, 19.3 mmol). The reaction mixture was heated at 65° C. for 3 hr. The MeOH was removed under reduced pressure and the aqueous residue was diluted with water (5 mL) and extracted with 5% MeOH in DCM (2×75 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 217 as a beige solid (144 mg, 67% over 3 steps). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.84 (s, 1H), 7.38-7.28 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.15 (s, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 3.36-3.25 (m, 2H), 3.22-3.08 (m, 3H), 3.07-2.99 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.93 (m, 1H), 1.88-1.65 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20]([N:23](CC2C=CC(OC)=CC=2OC)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(Cl)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 92.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (123 mg, 0.211 mmol) prepared in Example 23b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (85.0 mg, 54%) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[CH2:5][F:6].C(Cl)Cl.[OH-].[Na+]>CO>[NH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[CH:9]=1)[CH2:5][F:6]
Reactant: O=[N+]([O-])c1cc(I)cc(CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(I)cc(CF)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-iodo-5-nitrobenzyl fluoride (9.2 g, 32.7 mmol) described in Step C, in methanol (311 mL) was treated with TiCl3 (311 mL, >10 wt. % in 20-30 wt % HCl) and stirred at room temperature for 20 minutes. The reaction was poured into a separatory funnel containing 95:5 CH2Cl2 :MeOH and the aqueous layer was made basic with 15% aq. NaOH. The layers were separated and the aqueous layer was extracted with 95:5 CH2Cl2 :MeOH. The organic layers were combined, dried (MgSO4), filtered and concentrated to give an orange semi-solid. Purification by flash chromatography (3:1 to 1:1 hexane:methylene chloride) provided 3-amino-5-iodobenzyl fluoride as a tan solid: mp 48.5-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C:14](=[O:15])[C:6]3=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)c3cc(Cl)ccc3n2CCN1CCN1CCCC1
Temperature: 35 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of 8-chloro-10-phenyl-1,2,3,4-tetrahydropyrazino-[1,2-a]indole-1-one (6.0 g, 0.0202 mole) in dimethyl formamide (40 ml) is added over a period of 1/2 hour to a suspension of sodium hydride (1.4 g, 0.029 mole of a 50% dispersion in mineral oil) in dimethylformamide (20 ml). The mixture is stirred at about 35° C. for 1 hour. A solution of freshly distilled N-(β-chloroethyl)pyrrolidine (3.88 g, 0.029 mole) in dimethylformamide (10 ml) is added over a period of 1/4 hour. The reaction mixture is stirred at 50° C. for 18 hours, then cooled and poured into water (300 ml), this mixture is extracted with dichloromethane (4 portions, 100 ml each). The extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the filtrate is concentrated. The residue is recrystallized from heptane to give the above titled product, 6.15 g (77.3 % yield), melting at 134°-135.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1O
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccccc1OCCCCCc1ccccc1
Yield: 85.9 %

Procedure:
A solution of 10 g (80.56 mmol) of 2-hydroxybenzyl alcohol in 200 ml of dry acetonitrile is mixed with 27.45 g (120.83 mmol) of (5-bromopentyl)benzene from Example 26A and 12.25 g (88.61 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting organic phase is concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 18.7 g (81% yield) of a colorless solid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])([CH3:20])([CH3:19])[CH3:18].[I-].[Na+]>CC(C)=O>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][CH2:26][CH2:27][N:12]1[CH2:13][CH2:14][C:9]([C:15]#[N:16])([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#CC1(c2ccc(F)cc2F)CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 4-(2,4-difluorophenyl)-piperidine-4-carbonitrile (0.203 g, 0.914 mmol) in acetone (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (0.239 g, 1.00 mmol) potassium carbonate (0.505 g, 3.65 mmol) and sodium iodide (0.274 g, 1.82 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (20 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.259 g (75%) of the required product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:17]=[C:16](B(O)O)[C:12]2[O:13][CH2:14][CH2:15][C:11]=2[CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>COCCOC.CCO.COCCOC.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:8][C:9]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:12]2[O:13][CH2:14][CH2:15][C:11]=2[CH:10]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1cc(Br)cc2c1OCC2
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: [Cl-]
Solvent: CCO
Solvent: COCCOC
Product: Brc1cc2c(c(-c3ccncc3)c1)OCC2
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
4-Bromopyridine or hydrochloride salt thereof was dissolved in DME under argon and Pd(Ph3P)4 (3 mol %) was added. The mixture was stirred for 10 min at 50° C. To this solution was added (commercially available) 5-bromo-2,3-dihydrobenzo[b]furan-7-boronic acid dissolved in a minimum amount of EtOH/DME 1:2 followed by 2N Na2CO3. The reaction mixture was refluxed (110° C.) under stirring for 2 h. The flask was cooled to RT, the mixture was treated with sat. aq. NH4Cl solution and extracted with CHCl3. Evaporation and purification by SiO2 gel chromatography (hexane/ethyl acetate: 4/1) gave the title compound in 76% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH:15]1([CH2:21][NH:22][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (750 mg, ex Maybridge) in dichloromethane (15 ml) at −400 was added dropwise over 30 minutes a solution of cyclohexanemethanamine (0.35 ml, ex Lancaster) and triethylamine (0.41 ml) in dichloromethane (15 ml). Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed sequentially with water, 5% sodium bicarbonate solution and water, dried (MgSO4), evaporated and triturated with ether:hexane to afford 2-chloro-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (666 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:35][C@@H:36]([C:38]5[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=5)[CH3:37])=[O:34])[C:30]([OH:45])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O1COCO[CH2:47]1.OS(O)(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:45][CH2:47][N:35]([C@@H:36]([C:38]6[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=6)[CH3:37])[C:33](=[O:34])[C:31]=5[N:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)N[C@H](C)c4ccc(F)cc4)n3)cc12
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N([C@H](C)c3ccc(F)cc3)CO4)cc12
Yield: 20.2 %

Procedure:
(R)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-(1-(4-fluorophenyl)ethyl)-3-hydroxypicolinamide (80 mg, 0.13 mmol), 1,3,5-trioxane (114 mg, 1.26 mmol), H2SO4 (20 μl, 0.38 mmol) and sodium sulfate (159 mg, 1.26 mmol) in 1,2-dichloroethane (5 ml) were sealed in a tube. The mixture was microwaved at 80° C. for 1 h. 1N NaOH (10 ml) was added and the mixture extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. Preparative TLC gave (R)-2-(4-fluorophenyl)-5-(3-(1-(4-fluorophenyl)ethyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (17 mg, yield: 21%). MS (M+H)+: 647.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([O-:3])=[O:2]
Reactant: COC(=O)CCCCCBr
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1cc(OC)ccc1[N+](=O)[O-]

Procedure:
6-(2-isothiocyanoto-5-methoxphenoxy)hexanoic acid, represented as TB595 and shown in FIG. 3L was prepared by a number of steps. The first step involves the reaction of 2-nitro-5-methoxyphenol (1.69 g, 10 mmol) with methyl 6-bromohexanoate (2.08 g, 10 mmol) in dry dimethylformamide and anhydrous potassium carbonate (2.0 g, 14.5 mmol) at 60° C. for 12 hours to produce the intermediate ester, methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate. Hydrogenation of methyl 6-(2-nitro-5-methoxyphenoxy)hexanoate using palladium-on-carbon as catalyst afforded the isolation of methyl 6-(2-amino-5-methoxyphenoxy)hexanoate which was saponified in 10% water/ethanol (1:1) solution of potassium hydroxide to give 6-(2-amino-5-methoxyphenoxy)hexanoic acid in 95% yield. Finally, the reaction of 6-(2-amino-5-methoxyphenoxy)hexanoic acid (1.0 g, 3.9 mmol), thiophosgene (0.8 ml, 4.2 mmol), and pyridine (1.0 g, 7 mmol) in tetrahydrofuran at room temperature gave 0.9 g (78% yield) of the desired product as a colorless powder. The structure of the product was confirmed by NMR. Anal. Calcd for C14H17NO4S: C, 56.92; N, 4.74; S, 10.86.
Reaction SMILES: [I-].CN1C=CC=[CH2+]C1[C:9]([C@@:11]1([OH:36])[C@@H:15]([CH:16]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[OH:17])[O:14][C@@H:13]([N:24]2[CH:35]=[C:30]([C:31]([F:34])([F:33])[F:32])[C:28](=[O:29])[NH:27][C:25]2=[O:26])[CH2:12]1)=[O:10].C([O-])(O)=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+].C(O[CH2:54][CH3:55])(=O)C>O>[CH3:25][N:24]1[CH:55]=[CH:54][CH2:11][C:12]([C:9]([C@@:11]2([OH:36])[C@@H:15]([CH:16]([C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[OH:17])[O:14][C@@H:13]([N:24]3[CH:35]=[C:30]([C:31]([F:32])([F:34])[F:33])[C:28](=[O:29])[NH:27][C:25]3=[O:26])[CH2:12]2)=[O:10])=[CH:13]1
Reactant: CCOC(C)=O
Reactant: CN1C=CC=[CH2+]C1C(=O)[C@]1(O)C[C@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1C(O)C(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: O
Product: CN1C=CCC(C(=O)[C@]2(O)C[C@H](n3cc(C(F)(F)F)c(=O)[nH]c3=O)O[C@@H]2C(O)C(=O)C(C)(C)C)=C1

Procedure:
To a stirring solution of 100 mg of the product of Example 106 in a mixture of 20 mL of water and 20 ml of ethyl acetate were added 64 mg of NaHCO3 and 115 mg of Na2S2O4 under N2 gas. The resultant mixture was stirred at room temperature for 1 hour, then the organic layer was separated and washed with water. The extract was dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was triturated with a mixture of ether and n-hexane and the yellow needles which formed were collected by suction filtration (50 mg, 62%). The product melted at 168°-170° C. NMR analysis confirmed that the product had the structural formula: ##STR135##
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)=O.[H-].[Li+].[Al+3].[H-].[H-].[H-]>O1CCCC1>[CH3:17][C:15]1[CH:16]=[C:7]2[CH2:6][CH:5]([CH2:4][NH:3][CH3:1])[O:19][C:8]2=[C:9]2[C:14]=1[NH:13][C:12](=[O:18])[CH:11]=[CH:10]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 50 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
(+)-2-Formylaminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (460 mg, 1.78 mM) was dissolved in dry tetrahydrofuran (100 ml). To the solution, aluminum lithium hydride (135 mg, 3.57 mM) was added thereto. The mixture was dried while stirring in a bath of 50° C. in the atmosphere of nitrogen for 18 hours. The reaction mixture was cooled. A small amount of ethyl acetate was added. The solvent was distilled off under reduced pressure. 2N-caustic soda solution was added to the residue, followed by extraction with a solvent mixture of chloroform: methanol=10:1. The extract was dried, and the solvent was distilled off under reduced pressure. 360 mg of the title compound was obtained as a crude (+)-5-methyl-2-methylaminomethyl-2,3,6,7-tetrahydrofuro [2,3-f]quinoline-7-one (82.9%). The obtained crude was dissolved in methanol. 4N-HCl in 1,4-dioxane solution (0.4 ml) was added to the methanol solution of the crude, and the solution was concentrated. The resultant concentrate was recrystallized from methanol--ether, obtaining 276 mg of the title compound (66.7%) as yellow powder.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[CH3:22])[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[C:34](#N)C>CN(C)C=O>[CH3:22][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[CH:12]1[C:11]2[C:10](=[O:23])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:4](=[O:3])[N:13]1[CH3:34])[C:18]#[N:19]
Reactant: CC#N
Reactant: Cc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 6 mg, 0.16 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-methylbenzonitrile (example 55, 60 mg, 0.13 mmol) in acetonitrile (3 mL), and the mixture is stirred at room temperature for 20 min. Methyl idodide (16 μL, 0.26 mmol) is added, and the mixture is stirred over night, diluted with N,N-dimethylformamide (1 mL) and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 13 mg; ESI mass spectrum [M+H]+=440; Retention time HPLC: 0.65 min (X012_S01).
Reaction SMILES: O1CCOCC1.[ClH:7].[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][NH:30]C(OC(C)(C)C)=O)=[O:28])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>>[ClH:7].[NH:29]([C:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[CH:17][CH:16]=2)=[CH:25][CH:24]=1)=[O:28])[NH2:30]
Reactant: CC(=O)Nc1ccc(CCc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(CCc2ccc(CC(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
4M-Hydrogen chloride dioxane solution (1 ml, 4 mmol) was added to tert-butyl 2-({4-[(4-acetamidophenyl)ethyl]phenyl}acetyl)hydrazinecarboxylate (23 mg, 0.056 mmol), and the mixture was stirred at room temperature for 15 mins. The reaction mixture was concentrated under reduced pressure, dichloromethane was added, and the mixture was concentrated again, and hydrogen chloride gas was removed. The precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (18 mg, yield 98%) as a slightly yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[N:21](CC5C=CC(OC)=CC=5)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]>C(#N)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: COc1ccc(CN2CC(C)(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)OC2=O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CNC(=O)O4)cc3)oc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.1 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[3-(4-methoxybenzyl)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl}benzamide (598 mg, EXAMPLE 65) in 18.0 ml of acetonitrile and 6.0 ml of water was added 1.52 g of ceric ammonium nitrate. The mixture was stirred at room temperature for 15 h, and then concentrated in vacuo. The residue was dissolved in 10 ml of dichloromethane and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 2 column volumes to remove all the impurities. The column was then flushed with methanol (5 column volumes) to provide the title compound (242 mg, 52%) as a white solid. Mass spectrum (ESI) 419.1 (M+1).