Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13].Cl>CO>[CH2:12]([C:11]1[N:10]=[CH:8][NH:9][C:16](=[O:17])[CH:15]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(=O)[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium methoxide (4.19 kg, 77.6 mol) and formamidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5°-10° C. was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the temperature below 20° C. throughout the addition. The resulting mixture was stirred at room temperature overnight after which time the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure to ca. 10 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2×30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallised from the solution (2,4 kg, 70%) and was recrystallised from isopropanol to yield a product of m.p. 132°-134° C. Found: C,58.45; H,6.37; N,22.41; C6H8N2O requires: C,58.05; H,6.50; N,22.57%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:20](O)=[O:21])=[C:11]2[C:10]([C:27]([O:29][CH3:30])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:40]1([NH:45][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:11]=23)[C@@H:23]([CH3:26])[CH2:24][CH3:25])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (2R,3S)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylpentanoic acid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C26H38N4O5, 487; found, 487.7.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C[N:33]1[CH2:38][CH2:37][O:36][C:35]2[CH:39]=[C:40]([S:43](Cl)(=[O:45])=[O:44])[CH:41]=[N:42][C:34]1=2>>[CH2:30]([O:29][CH2:28][C@@:10]12[CH2:9][N:8]([S:43]([C:40]3[CH:41]=[N:42][C:34]4[N:33]=[CH:38][CH2:37][O:36][C:35]=4[CH:39]=3)(=[O:45])=[O:44])[CH2:17][CH2:16][C:15]1=[CH:14][C:13]1[N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:12]=1[CH2:11]2)[CH3:31]
Reactant: CN1CCOc2cc(S(=O)(=O)Cl)cnc21
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cnc3c(c1)OCC=N3)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonyl chloride. LCMS (Method C): 540 (M+H)+, Retention time 11.9 minutes.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:17][C:14]1[S:15][C:16]2[C:8]([CH:6]3[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]3)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:25]
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-bromo-isonicotinic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as off-white powder. MS: m/e=452(M+H+).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[CH:6]1[C:11](O)=[CH:10]C=[C:8](C)[CH:7]=1.CI.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>[Pd](Cl)Cl.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(C)=O
Reactant: Cc1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CI
Product: CC(=O)Oc1ccccc1

Procedure:
A 300-ml autoclave equipped with an agitator was charged with 59.2 g of methyl acetate, 104 g of p-cresol, 1.8 g of palladium chloride, 31.5 g of methyl iodide and 5.8 g of triphenylphosphine, and the reaction was carried out at 195° C. and a carbon monoxide pressure of 28 kg/cm2 gauge (total pressure of 38 kg/cm2 gauge). The yields of acetic acid and phenyl acetate were 95.8% and 95.6%, respectively. The reaction was repeated several times, and the resulting reaction product liquids were collected and used in Example 13.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In analogy to the procedure described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with (2-aminoethyl)-carbamic acid tert-butyl ester in dioxane at 120° C. overnight to give {2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester as a white solid; MS: 410 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C.C(Cl)Cl>[Cl:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2[nH]c(=O)cnc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Cl)cnc2c1
Temperature: 100 °C

Procedure:
2-Oxo-1,2-dihydroquinoxaline-6-carbonitrile was suspended in POCl3 (25 mL) and DMF (10 drops) was added. The mixture was heated at 100° C. for 2 h, cooled and concentrated under reduced pressure to leave a black residue. The residue was dissolved in CH2Cl2 (200 mL), washed with satd aq NaHCO3 (25 mL) and brine (25 mL) and dried over Na2SO4. Removal of the solvent left an off white solid (4.50 g). A 0.50-g portion was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-50% EtOAc in hexanes gradient to afford 2-chloroquinoxaline-6-carbonitrile (118 mg). LC-MS Method 1 tR=1.42 min, m/z=190.
Reaction SMILES: I[Br:2].BrBr.[F:5][C:6](I)([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>>[F:5][C:6]([Br:2])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: BrI
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: BrBr
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Reaction time: 5 h
Yield: 92.5 %

Procedure:
With reference to FIG. 1, and H-shaped tube equipped with a Dimroth condenser and a Dimroth condenser having an IBr withdrawing cock was attached to a 500-ml four-necked flask. Into the flask were placed 200 ml (747 mM) of perfluorooctyl iodide (PFOI) and 5.0 ml (97.1 mM) of bomine, and the mixture was heated at 150° to 155° C. and irradiated with a 500-W visible light lamp. After the reaction mixture started to reflux, 49.5 ml (972 mM) of bromine was added dropwise to the mixture at a rate of 0.2 ml/min over a period of about 4 hours. The resulting IBr was drawn off at a suitable time through the IBr withdrawing Dimroth condenser. The reaction was continued for 5 hours, and the reaction mixture was thereafter cooled and washed with a 5% aqueous solution (200 ml) of sodium hydroxide to obtain 344.9 g (92.5% in yield) of perfluorooctyl bromide.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.[CH3:15][N:16]=[C:17]=[S:18]>C(#N)C>[CH3:15][NH:16][C:17]([NH:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[S:18]
Reactant: Cc1cnc2c(c1)CCCC2N
Reactant: CN=C=S
Agent: Cl
Solvent: CC#N
Product: CNC(=S)NC1CCCc2cc(C)cnc21
Yield: 99.9 %

Procedure:
The 8-amino product of Example 3 (free base) (3 g.) was dissolved in acetonitrile (30 ml.) and the solution treated with methylisothiocyanate (1.35 g.) and heated at reflux for 2 hours. The solvent was removed in vacuo and the residual solid recrystallised from absolute ethanol to give the title compound as colourless needles (3 g.) m.p. 113° C.
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:15]=[CH:14][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[S:5][CH:6]=[C:7]([NH:9][C:10]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)[N:17]=3)=[O:34])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cccc(NC(=O)Nc3csc(C4CC4)n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(C2CC2)n1

Procedure:
In a manner similar to that described in Example 2,2-cyclopropylthiazole-4-carbonylazide (133.0 mg, 0.686 mmol) and tert-butyl 4-[2-(6-amino-pyridin-2-yloxy)-ethyl]-piperidine-1-carboxylate (220.0 mg, 0.686 mmol) were heated in toluene (20 mL) to give the BOC-protected product as a yellow oil. In a similar manner to Example 274, tert-butyl 4-(2-{6-[3-(2-cyclopropyl-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylate (7.6 mg, 0.016 mmol) was heated in CH2Cl2 (10 mL) in the presence of TFA (2 mL) to give the product as yellow oil. MS m/z: 388.3 (M+H). Calc'd. for C19H26N5O2S-388.2.
Reaction SMILES: C([N:8]([C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[C@H:9]([C:38]([OH:40])=[O:39])[CH2:10][O:11][C:12](=[O:37])[CH:13]([NH:26]C(OCC1C=CC=CC=1)=O)[CH:14]([O:19]C1CCCCO1)[C:15]([F:18])([F:17])[F:16])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:26][CH:13]([CH:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:12]([O:11][CH2:10][C@@H:9]([C:38]([OH:40])=[O:39])[NH:8][C:41](=[O:46])[C:42]([F:44])([F:43])[F:45])=[O:37]
Reactant: O=C(NC(C(=O)OC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)C(F)(F)F)C(OC1CCCCO1)C(F)(F)F)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O)C(O)C(F)(F)F
Yield: 94 %

Procedure:
A solution of benzyl N-trifluoroacetyl-O-[2-benzyloxycarbonylamino-3-(2-tetrahydropyranyloxy)-4,4,4-trifluoro-1-oxobutyl]-L-serine (1.36 g) and p-toluenesulfonic acid monohydrate (39 mg) in methanol (14 ml) was stirred overnight. The solvent was distilled off and the residue was diluted with ethyl acetate and washed successively with 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was dissolved in acetic acid (50 ml) and 10% palladium on activated carbon (500 mg) was added. The mixture was hydrogenated under hydrogen at 40 psi at room temperature for an hour. The solvent was distilled off and the residue was lyophilized to give O-(2-amino-3-hydroxy-4,4,4-trifluoro-1-oxobutyl)-N-trifluoroacetyl-L-serine (685 mg).
Reaction SMILES: [CH3:1]I.[H-].[Na+].[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11]([CH2:26][OH:27])=[C:10]([CH:28]([CH3:30])[CH3:29])[N:9]=1)([CH3:7])[CH3:6].O>O1CCCC1>[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:11]([CH2:26][O:27][CH3:1])=[C:10]([CH:28]([CH3:29])[CH3:30])[N:9]=1)([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
0.57 ml (9.2 mmol) of methyl iodide and, at -50° C. 327 mg (10.9 mmol) of 80% strength sodium hydride are added under a nitrogen atmosphere to 3 g (8.4 mmol) of the compound from Example 4 in 100 ml of dry tetrahydrofuran. The mixture is stirred for 2 hours and the temperature is allowed to rise to 25° C. in the course of this. Water is cautiously added to the mixture and it is extracted several times using ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.S(Cl)(Cl)=O.[CH3:29]O>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([O:24][CH3:29])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: O=C(O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Temperature: 70 °C
Yield: 38 %

Procedure:
2-(2-Fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylic acid (500 mg, 1.53 mmol) was dissolved in methanol (20 mL) at −5° C.-0° C., thionyl chloride (0.2 mL, 2.40 mmol) was added dropwise. The mixture was heated at 70° C. for 3 h., then evaporated and the residue was adjusted to pH=9 by NaHCO3, and extracted with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and evaporated to give methyl 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (200 mg, yield 38%) as white solid. LC-MS (ESI) m/z: 341 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[N:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C.Br[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH2:39][CH3:40]>O>[CH2:39]([O:38][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:28]=1[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[C:32]([O:34][CH3:35])=[O:33])[CH3:40]
Reactant: CCOc1cc(C(=O)OC)ccc1Br
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1cnn(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (183 mg, 0.88 mmol), potassium phosphate (374 mg, 1.76 mmol) and dichloro(1,1-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct (9.6 mg, 0.012 mmol) were added to an acetonitrile solution (3 mL) of methyl 4-bromo-3-ethoxybenzoate (152 mg, 0.59 mmol), and stirred overnight at 100° C. The reaction liquid was cooled to room temperature, and water was added to it. This was extracted with ethyl acetate, washed with saturated saline water, and dried with magnesium sulfate. The solution was filtered, and concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=50/50) to obtain the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH:19]1[CH2:24][CH2:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]3=[O:41])=[CH:27][CH:26]=2)=[CH:21][CH2:20]1>ClCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:19]2[CH2:24][CH2:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]4=[O:41])=[CH:27][CH:26]=3)=[CH:21][CH2:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(S(=O)(=O)c4ccc(C)cc4)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (202 mg), followed by p-toluenesulfonyl chloride (171 mg) were added to a stirred suspension of the TFA salt of Example 2 (322 mg) in dichloromethane (10 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture had become a solution and the reaction was complete. The solution was washed with 2N HCl, water, saturated NaHCO3 and saturated NaCl. The organic phase was dried over anhydrous Na2SO4 and evaporated to give a crystalline solid which was triturated with ether to give the title compound. Yield=306 mg, 87%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccnc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Diethyl azodicarboxylate (DEAD) (4.26 mL, 27.0 mmol) was added drop-wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (6.00 g, 18.0 mmol), 4-hydroxyquinoline (3.92 g, 27.0 mmol) and Ph3P (7.09 g, 27.0 mmol) in THF (90 mL) at room temperature. The mixture was stirred at room temperature for 1 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH, 95:5) to give the title compound (6.22 g, 75% yield) as a white solid: MS (ESI) m/z 460/462.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH:19]([CH3:21])[CH3:20])=[O:5])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]1[CH:19]([CH3:20])[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(C(C)C)[nH]c2cc([N+](=O)[O-])c(F)cc12
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2cc([N+](=O)[O-])c(F)cc12

Procedure:
The title compound was prepared from ethyl5-fluoro-2-isopropyl-6-nitro-1H-indole-3-carboxylate (Compound 168) and benzyl bromide by General Procedure J.
Reaction SMILES: IC.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][OH:15])[CH:8]=[CH:7]2.[H-].[Na+].[CH3:18]N(C=O)C>O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:14][O:15][CH3:18])[CH:10]=2)[CH:5]=1
Reactant: CN(C)C=O
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1ccc2cc(Br)ccc2c1

Procedure:
Iodomethane (18.96 g, 133.6 mmol) was added dropwise to ice-cooled mixture of (6-bromo-naphthalen-2-yl)-methanol (15.84 g, 66.8 mmol), sodium hydride 60% in oil (3.84 g, 100.2 mmol), and DMF (100 ml). Water was added and the product was filtered. Yield 16.7 g (99%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:36]=[C:37]([C:41](=[O:56])[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=1.[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[CH2:63]O>O1CCCC1>[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[CH2:63][O:34][C:35]1[CH:36]=[C:37]([C:41](=[O:56])[CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccsc1CO
Reactant: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1cccc(OCc2sccc2C)c1)c1ccccc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
A solution of triphenylphosphine (1.13 g) in tetrahydrofuran (30 mL) is treated with diisopropyl azodicarboxylate (0.84 mL) at 0-5° C. The suspension is then treated with methyl (RS)-5-(3-hydroxyphenyl)-5-oxo-4-(2-methylphenyl)pentanoate (671 mg) and 3-methyl-2-thienylmethanol (275 mg), and stirred at 5° C. for 15 minutes. The solution is evaporated and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (5:1 v/v), to give methyl (RS)-5-[3-(3-methyl-2-thienylmethoxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (350 mg), in the form of an oil. [NMR(CDCl3):- 2.0-2.5(4H,m), 2.25(3H,s),2.5(3H,s), 3.65(3H,s), 4.8(1H,m),5.1 (2H,q),6.85-7.5(10H)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:27][C@@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])[C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(F)(F)F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (±)-4-oxo-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2b) (1 equiv.) in toluene is added (R)-(+)-α-methylbenzylamine (1 equiv.) and catalytic amount of p-toluenesulfonic acid. The solution is heated to reflux under a Dean-Stark apparatus. After 12 hr, the reaction is cooled to RT, washed with 10% aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue is dissolved in EtOH and NaBH4 (1 equiv.) is added. After 12 h, the reaction is concentrated and the residue is dissolved in 1 N HCl. The solution is neutralized with 6 N NaOH and extracted with EtOAc. The organic fraction is dried over Na2SO4 and concentrated under vacuum. The crude product is purified by chromatography on silica gel to afford the title compound. The three other diastereomers are also separated.