Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22]Cl)=[CH:16][C:15]=1[O:24][CH3:25]>CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C.O>[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: COc1cc(CCl)cc(OC)c1Br
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O
Product: COc1cc(COC2CCC2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of cyclobutyl alcohol (4.16 g, 57.7 mmol) and DMF (30 mL) was added sodium hydride (60% oil dispersion: 2.31 g, 57.7 mmol) while cooling on ice, and the mixture was stirred at room temperature for one hour. To the mixture was gradually added dropwise a mixture of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.47 g, 9.3 mmol) and DMF (30 mL), and the mixture was stirred at room temperature for one hour. Water was added to the mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.39 g, 7.94 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[C@H:29]12[CH2:35][C@H:32]([CH2:33][CH2:34]1)[CH2:31][CH:30]2[NH2:36]>>[CH3:28][N:4]1[C:3]([CH2:2][NH:36][CH:30]2[CH2:31][C@H:32]3[CH2:35][CH:29]2[CH2:34][CH2:33]3)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NC1C[C@H]2CC[C@@H]1C2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3C[C@@H]4CCC3C4)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with (1R,4S)-bicyclo[2.2.1]heptan-2-amine via General Procedure E to give 16 mg of 272 following reverse phase purification. MS (Q1) 473.3 (M)+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].CN(C)CCN(C)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:50])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g, 2.8 mmol) and tetramethylethylene diamine (0.5 g, 4.3 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (1.2 mL, 3.0 mmol, 2.5 M) at -78° C. After 30 minutes, N-fluorobenzenesulfonimide (0-8 g, 3.2 mmol) is added to the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through column chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[C:29]([O:39][CH3:40])[N:28]=3)[CH2:12]1)[C:8](=[O:41])[NH:7]2)=[O:5])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH3:40][O:39][C:29]1[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:41])[CH2:23]4)[CH2:12]2)[CH:32]=[C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(OC)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of compound 13d (470 mg, 0.83 mmol) in a mixture of THF methanol 1:1 (30 ml) was added 1 M LiOH solution (10 ml) and the mixture was stirred for four days at room temperature. A 5% solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated on silica gel. The product was isolated by silica gel chromatography eluted with DCM methanol, (400 mg, 88%), (M+H)+535.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.Cl.[C:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]([O:14][C:15](=[O:19])[C@@H:16]([NH:17][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.179) in N,N-dimethylformamide (DMF) (3 mL) was added alanine tert-butyl ester hydrochloride (0.22 g), diisopropylethyl amine (0.27 mL) and HOBT (0.41 g) before cooling to 0° C. and the reaction mixture was then treated with EDC HCl (0.32 g). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18 hrs before being diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the sub-title compound as a colourless oil (0.263 g, 73%): 1H NMR 400 MHz CDCl3 1.50 (9H, s), 1.51 (3H, d, J 7.2), 3.70 (1H, m), 7.28 (2H, s), 7.78 (1H, d, J 7.6), 11.49 (1H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:16][S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 3-benzyloxy-5-methylphenol (400 mg, 2.0 mmol), as prepared in step a of Example 3, in methylene chloride (10 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.4 mL) and benzenesulfonyl chloride (354 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (675 mg, 95%). 1H-NMR(300 MHz, CDCl3) δ 2.24 (s, 3H), 4.91 (s, 2H), 6.40 (t, 1H), 6.43 (s, 1H), 6.68 (s, 1H), 7.36 (m, 5H), 7.52 (t, 2H), 7.64 (d, 1H), 7.83 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)=[O:19])[CH:16]=3)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[OH:19])[CH:16]=3)[N:11]([CH3:26])[C:10](=[O:27])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)s3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(O)c3ccc(Cl)s3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a suspension of 4-(3-chloro-phenyl)-6-(5-chloro-thiophene-2-carbonyl)-1-methyl-1H-quinolin-2-one (58 mg, 0.154 mmol) in MeOH (1 ml) was added sodium borohydride as solid (NaBH4, 7 mg, 0.185 mmol) at 0° C. The reaction mixture was stirred at 0° C. for one hour after which time it was partitioned between chloroform and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give an off-white solid (49 mg, 78.5% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: NCCN1CCCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(CC(C)C)C(=O)NCCN1CCCCC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of (±)-2-[(acetylthio)methyl]-4-methylpentanoic acid in 40 ml of THF is cooled to 5° C., followed by the dropwise addition of triethylamine (1.0 g) in 5 ml of THF. This solution is cooled to -5° C. and ethyl chloroformate in 4 ml of THF is added dropwise at -5° to 0° C. It is stirred for 30 minutes and N-(2-aminoethyl)piperidine in 30 ml of THF is added dropwise. The reaction mixture is stirred at 20° C. for 4 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue is dissolved in ether and washed with aqueous NaHCO3. Ether is dried with MgSO4, filtered and concentrated in vacuo to yield 2.1 g of crude product. This crude is absorbed on a 20-g pad of alumina act II and washed through with ether to yield 1.4 g of product which crystallizes from pentane, melting point 47°-50° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12][C:13]1[CH:14]=[C:15]([NH2:22])[C:16](=[CH:20][CH:21]=1)[C:17]([OH:19])=[O:18]>CO.O>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:22][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:14]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccccc1Nc1cc(Br)ccc1C(=O)O
Yield: 70 %

Procedure:
Reaction of methyl 2-iodobenzoate and 4-bromoanthranilic acid by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 4-bromo-2-[(2-methoxycarbonyl-phenyl)amino]benzoic acid (70%), mp (MeOH/H2O) 218-219.5° C. 1H NMR [(CD3)2SO] δ 3.85 (s, 3 H, COOCH3), 7.08-7.12 (m, 2 H, 2×ArH), 7.50 (d, J=1.9 Hz, 1 H, H-3), 7.57 (d, J=3.8 Hz, 3 H, 2×ArH), 7.84 (d, J=8.4 Hz, 1 H, ArH), 7.93 (d, J=7.7 Hz, 1 H, ArH), 10.80 (s, 1 H, NH), 13.33 (br s, 1 H, COOH). Anal. (C15H12BrNO4) C, H, N.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[N:11]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1COCCN1
Solvent: O
Product: c1ccc2c(N3CCOCC3)nc(N3CCOCC3)nc2c1

Procedure:
Eight grams of 2,4-dichloroquinazoline was cautiously added to 25 ml of morpholine; a vigorous reaction ensued upon mixing. After the initial reaction subsided, the mixture was then heated to 110° overnight. The reaction mixture was poured into water, and the resulting aqueous solution was extracted with several portions of ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from aqueous ethanol, giving 8 g of 2,4-bismorpholinoquinazoline; m.p. 172°-174°. The following analytical data were obtained:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][N:10]=[C:11]([C:28]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])[CH2:29][Br:30])[C:12]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[CH:18]([C:23]([OH:25])=[O:24])[CH:19](O)[CH2:20][S:21][C@H:16]12)=[O:13].C([O-])(=O)C.[Na+].C([O-])(=O)C.[K+].[Cl-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C>[CH3:8][O:9][N:10]=[C:11]([C:28]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])[CH2:29][Br:30])[C:12]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 121.4 %

Procedure:
Acetic anhydride (27.3 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 30 g) in dry tetrahydrofuran (300 ml) at room temperature and stirred at 28° C. for 30 minutes. After adding sodium acetate (4.0 g) and potassium acetate (4.7 g) to the solution, the solution was stirred at 28° to 30° C. for 3 hours. The resultant solution was added to a solution of ethyl acetate (300 ml) and a saturated aqueous solution of sodium chloride (300 ml), and adjusted to pH 2.0 with 20% sulfuric acid. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 ml) twice. The organic layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. After treating the solution with activated charcoal, the solution was evaporated in vacuo. n-Hexane was added to the residue and decanted to give the oil (35.1 g) of 7-(2-methoxyimino-3,3-diethoxy-4- bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36](C)(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].CO.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:47])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: COC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 83.5 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 83.5% of theory, C29H31N5O3 (497.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=498; (M+H+Na)++=260.7.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.O.CCCCCC>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][I:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 6.6 g (25 mmol) of triphenylphosphine in 125 mL of CH2Cl2 was added 1.7 g (25 mmol) of imidazole followed by 6.3 g (25 mmol) of iodine, and the mixture was stirred at rt for 30 min, after which 2.0 g (8.32 mmol) of 1-t-butoxycarbonyl-4-(2-hydroxyethyl) piperidine (from EXAMPLE 113, Step A) was added in CH2Cl2 and the mixture was stirred overnight at rt . The mixture was diluted with H2O, the phases were separated, and the organic phase washed with sat'd NaCl and 0.25 M Na2SO3 solution. The aqueous phase was then extracted 3× with CH2Cl2, and the combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated to provide a white solid. The solid was taken up in hexane, filtered and washed with hexane. The filtrate was concentrated. Flash chomatography on 100 g of silica gel using 17:3 v/v hexanes/EtOAc as the eluant afforded 2.8 g (96%) of the title compound: 1H NMR (500 MHz) δ 1.11 (dq, J=4.4, 8.2, 2H), 1.46 (s, 2H), 1.55-1.63 (m, 1H). 1.66 (d, J=12.6, 2H), 1.78 (q, J=7.1, 2H), 2.65-2.75 (2H), 5.22 (2H), 3.22 (t, J=7.1, 2H), 4.1 14.15 (5H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:19]([O-:21])=[O:20])=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[N:9]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(Cl)Cl>>[C:22]([O:17][CH2:16][C@H:15]([N:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]=2[N+:19]([O-:21])=[O:20])[C:10]1=[O:14])[CH3:18])(=[O:24])[CH3:23]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with (R)-6-cyclopropyl-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (30 mg, 0.0001 mol), acetic anhydride (0.015 mL, 0.00016 mol), pyridine (0.015 mL, 0.00019 mol) and methylene chloride (4 mL, 0.06 mol) and the reaction stirred at room temperature over night. The solvent was then removed and the product was taken to the next step without purification. MS m/z=331.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=O)[CH2:13][C:14]([O:16]CC)=O.FC(F)(F)C([O-])=O.[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C@@H:38]([NH2+:40][NH2:41])[CH3:39])=[CH:34][CH:33]=1)=[O:31])[CH3:28]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]1[CH2:13][C:14](=[O:16])[N:40]([C@H:38]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:33][CH:34]=2)[CH3:39])[N:41]=1
Reactant: CCOC(=O)CC(=O)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1ccc([C@H](C)[NH2+]N)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc([C@H](C)N2N=C(c3cc(C(F)(F)F)ccc3F)CC2=O)cc1

Procedure:
Ethyl 3-[2-fluoro-5-(trifluoromethyl)phenyl]-3-oxopropanoate (3 g, 9.7 mmol) and {(1S)-1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium trifluoroacetate (2.64 g, 8.2 mmol) were heated in dry acetonitrile (150 ml) to 85° C. for 8 hr. Solvent was evaporated and the residue purified by flash column chromatograph (SiO2, 25% ethyl acetate in hexanes) to give ethyl 4-((1S)-1-{3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}ethyl)benzoate as a white solid. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1, 3H); 1.82 (d, 7.2 Hz, 3H); 3.81 (dd, J=3 Hz, 23.9 Hz, 1H); 3.87 (dd, J=3 Hz, 23.9 Hz, 1H); 4.36 (q, J=7.1 Hz, 2H); 5.60 (q, J=7.2 Hz, 1H); 7.25 (t,J=9.5 Hz, 1H); 7.51 (d, J=8.4 Hz, 2H): 7.66 (br, 1H); 8.03 (d, J=8.4 Hz, 2H); 8.25 (dd, J=1.8 Hz, 6.4 Hz, 1H). MS C21H18F4N2O3
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:7](=O)[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:7](=[N:21][C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)C1(C)COCCC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)COCCC1=N[C@H](C)c1ccccc1

Procedure:
Methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate (2.33 g, 13.53 mmol) was dissolved in toluene (150 mL) and treated with R-(+)-α-methylbenzylamine (3.96 mL, 2.3 eq) and ytterbium (III) trifluoromethanesulfonate (252 mg, 0.03 eq). The mixture was heated to reflux under Dean-Stark conditions overnight, and then concentrated to provide crude methyl 3-methyl-4-((R)-1-phenylethylimino)-tetrahydro-2H-pyran-3-carboxylate that was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:24])[CH3:23]
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
20 grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril are mixed with 15 ml of acetic anhydride and 10 ml of acetic acid and heated for 5 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from Ethanol to obtain 5-[3-(4-acetylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 143°-145° C.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:22]([NH:29][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)N1CCN(C(=O)c2ccc(CNCc3ccccc3)cc2)CC1

Procedure:
To a solution of the product of Example 12 (150 mg) and benzylamine (0.062 mL) in DCM (5 mL) was added acetic acid (0.03 mL) and sodium triacetoxyborohydride (165 mg). After 16 h the reaction was treated with 1 N NaOH (20 mL) and extracted with DCM (3×20 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic ammonia-DCM) to give the title compound as an oil (150 mg).