Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(Cl)(Cl)Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1(O)[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1.O>C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([F:7])[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2Cl)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(F)(c2ccccc2Cl)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 5.26 mL of diethylaminosulfur trifluoride was added to chloroform (160 mL) solution of 5.51 g of benzyl 4-(2-chlorophenyl)-4-hydroxypiperidine-1-carboxylate at −78° C., and stirred for 1 hour at −78° C. Water was added to the reaction liquid, and extracted with chloroform. The chloroform layer was dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 150 mL of acetone/water (2:1) mixture. 15.9 mL of aqueous 0.05 M osmium tetroxide solution and 3.73 g of N-methylmorpholine N-oxide were added thereto, and stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 2.11 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH:11]([CH3:15])[CH2:12][CH:13]=O.[NH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:17]([N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])[CH:13]=[CH:12][C:11]=1[CH3:15]
Reactant: COc1ccc(C(=O)C(C)CC=O)c(Cl)c1
Reactant: NN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C)ccn2N2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
A mixture of 4-(2-chloro-4-methoxyphenyl)-3-methyl-4-oxobutanal (6.40 g, 27.0 mmol) and N-aminophthalimide (5.32 g, 29.0 mmol) in HCl (5N, 3.90 mL) and dioxane (100 mL) was heated at 100° C. for 1 h. After cooling down to room temperature, the mixture was concentrated in vacuo and the residue was recrystalized from CH2Cl2/hepatene to give 9.22 g (95%) of pink solid as the title compound: mp 202.0–208.5° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.95–7.86 (m, 4H), 7.17 (d, J=8.6 Hz, 1H), 7.01 (d, J=3.1 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 6.82 (dd, J=8.6, 2.6 Hz, 1H), 6.20 (d, J=3.1 Hz, 1H), 3.77 (s, 3H), 1.98 (s, 3H); IR (diffuse reflectance) 2072, 2014, 1981, 1906, 1747, 1463, 1293, 1275, 1214, 1047, 881, 820, 719, 712, 705 cm−1; HRMS (FAB) calcd for C20H15N2O3Cl+H 367.0849. found 367.0832. Anal. Calcd for C20H15N2O3Cl: C, 65.49; H, 4.12; N, 7.64. Found: C, 65.16; H, 3.99; N, 7.58.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.O1CCCC1>[O:9]=[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][N:3]1[NH:2][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NN1CCCNC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NN1CCCNC1=O)OCc1ccccc1

Procedure:
3-Aminotetrahydro-2(1H)-pyrimidinone, monohydrochloride (30 g, 0.198 mol) was dissolved in a mixture of 240 ml water and 200 ml tetrahydrofuran. The pH was adjusted to 8.5 and benzylchloroformate (33.8 g, 0.198 mmol) was added dropwise while keeping the pH between 8 and 9. After the pH remained constant, the mixture was stirred for an additional hour. The tetrahydrofuran was removed in vacuo and the resulting crystals were filtered off with suction, triturated with ether and dried in vacuo. Yield 35.6 g, melting point 161°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-4-hydroxyphenylacetate and 1,4-dibromobutane (0.021 g, 0.044 mmol) in 0.5 mL of methanol was added 5N NaOH soln (0.04 mL, 5 eq) at rt. The reaction mixture was heated initially with a heat gun to reflux in order to dissolve the starting material. After heating, the reaction mixture stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc and 0.1N HCl (5 mL). The organic layer was separated from the aqueous portion, and washed with 0.1N HCl (5 mL) followed by 10 mL brine. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:20][CH:19]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:27]([CH2:26][CH2:25][CH2:24][C:21]3[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=3)[C:28]2=[O:29])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: N#Cc1cccc(Nc2ncccc2C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-cyanophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(4-pyridyl)pentanoate (1.2 eq., prepared in Synthetic Example 10) and LDA (1.2 eq.) to obtain 1-(3-cyanophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 202 to 203.5° C./DMF.
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.[OH:28][S:29]([O-:32])(=O)=O.[K+].OOS([O-])=O.[K+].[CH3:40]O>O>[CH3:40][S:29]([C:7]1[CH:6]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:10]2=[O:27])[CH:4]=[CH:3][CH:8]=1)(=[O:32])=[O:28]
Reactant: CSc1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Reactant: O=S(=O)([O-])O
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
1-(3-Methylthiophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (250 mg, 0.664 mmole), prepared, e.g., as described in Example 5B, was dissolved in methanol (3 ml) and cooled to 0° C. To this solution, a 50% solution of 2KHSO5. KHSO4.K2SO4 in H2O, (this reagent is commercially available under the trademark of "OXONE®" from the Aldrich Chemical Company), (1.22 g, 1.99 mmole) was added. A cloudy slurry was formed and stirred at room temperature for 4 hours. The reaction mixture was diluted by adding H2O (2.4 ml) and extracted three times with methylene chloride (3×5 ml). The organic phases were combined and dried over Na2SO4, followed by filtration. The solvent was removed and the residue was dissolved in ethyl acetate/ethyl ether. The product was recrystallized out of the solution yielding 190 mg (0.465 mmole, 79% yield) of 1-(3-methylsulfonylphenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (mp 254°-256° C.) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[CH2:21][O:22][CH2:23][O:24][CH3:25])CCC.C(OCC)(=O)C.O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2[N:5]=[N:6][CH:7]=[C:2]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(Cl)cnn2)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
5-Chloro-3-(3-chloro-4-fluoro-phenyl)-pyridazine (535 mg, 2.2 mmol) and bis-(triphenylphosphine) -palladium(II)-dichloride (145 mg, 0.22 mmol) were treated with a solution of tributyl-methoxymethoxymethyl-stannane (Sawyer J. S.; Kucerovy A.; Macdonald T. L.; McGarvey G. J. J. Am. Chem. Soc. (1988), 110, 842-853) (964 mg, 2.64 mmol) in DMF (5.3 ml). The mixture was heated at 100° C. for 4 hours then cooled to room temperature and a saturated KEF solution (5.3 ml) was added. The mixture was stirred for 30 minutes at room temperature and ethyl acetate and water were added. The mixture was filtered and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 7:3) to provide 3-(3-chloro-4-fluoro-phenyl)-5-methoxymethoxymethyl-pyridazine (370 mg, 60%) as a pale yellow solid, MS: m/e=283.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:14]#[N:15].CN1C(=O)CCC1>C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Yield: 46.2 %

Procedure:
To a mixture of methyl 3-bromo-4-hydroxybenzoate (1.78 g, 7.70 mmol) and copper(I) cyanide (0.897 g, 10.02 mmol) was added NMP (10 mL). The mixture was heated to 200° C. for 2 h under microwave irradiation. The mixture was diluted with ethyl acetate and quenched with 1 N aqueous HCl solution. After the addition of brine, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography. The combined fractions were concentrated under reduced pressure and triturated with cold water to provide the title compound as an off-white solid (0.63 g). LCMS m/z=178.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3H), 6.55 (bs, 1H), 7.04 (d, J=8.72 Hz, 1H), 8.15 (dd, J=8.72, 2.15 Hz, 1H), 8.23 (d, J=1.89 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12>CN(C)C(=O)C.CC1CCCO1>[Cl:1][C:2]1[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 2.59 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.08 g, 2.85 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.46 g, 3.68 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL) and saturated NaCl (2×10 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([CH3:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:22][C:21]1[C:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=2)=[O:11])=[CH:13][C:14]2[C:15]([CH3:26])([CH3:25])[CH2:16][CH2:17][C:18]([CH3:23])([CH3:24])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalene-2carbonyl)-benzoic acid methyl ester (820 mg, 2.25 mmol) in 10 mL of THF and 10 mL of MeOH was added NaOH (22 mL of 1N solution, 22 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified with HCl (23 mL of 1N solution, 23 mmol). The product was extracted with CH2Cl2 twice and EtOAc twice. The combined organic fraction was dried over Na2SO4, filtered and was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:13]=1.[CH3:14][NH2:15]>O1CCCC1>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
6-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (200 mg, 1.104 mmol) was dissolved in dry tetrahydrofuran (THF) (10 mL), at which time methyl amine (3.31 mL, 6.63 mmol) was added. The reaction was stirred at room temperature for 1 h, then concentrated under vacuum. The crude product was purified on silica (Biotage, 40% EtOAc/hexene) to afford the title compound (120 mg, 65%) as a white solid. LC-MS (ES) m/z=169.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: NCCc1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.87 g of (3-chloro-2-fluoro-phenyl)-acetonitrile (11 mmol) were dissolved in 18 ml THF and cooled down to 0° C. under nitrogen. 58 ml of a 1M borane-THF complex solution in THF (58 mmol) were then added dropwise over 20 min by keeping the temperature between 0 to 2° C. After addition the reaction mixture was stirred at rt for additional 20 min, and refluxed for 21 h. The reaction mixture was then cooled down to 0° C. and treated between 2 and 5° C. with 13 ml methanol over a period of 35 min. After 1 h refluxing the reaction mixture was concentrated, the residue dissolved in DCM and the amine extracted twice with 1N aqueous HCl. The combined aqueous phases were then treated with concentrated NaOH to adjust the pH to 12, and then extracted twice with DCM. The combined organic phases were then washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo leading to 1.6 g colorless oil. This was dissolved in 50 ml diethylether, treated with 5 ml 2.6N HCl in diethylether, stirred at rt for additional 60 min, filtered and dried under high vacuo, leading to 1.6 g white solid (69%). MS (ISP) 174.2 (M+H)+.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=2)=[N:16][C:15]([Br:26])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh].C1COCC1>[Br:26][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:23]3[CH:22]=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2cccc(C=O)c2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(C=O)cc12
Temperature: 80 °C
Yield: 58 %

Procedure:
1,2-Dichloroethane (1.7 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(3-formylphenyl)isonicotinate (903 mg, 2.50 mmol), rhodium octanoate dimer (156 mg, 0.20 mmol) and crushed 4A° molecular sieves (0.9 gm) in an flask. This was heated at 80° C. for 18 hr. The reaction was diluted THF and filtered. The collected solid was washed with multiple portions of boiling THF to complete extraction of the product. The solvent was removed from the combined filtrates, the residue was suspended in MeOH, and the product was collected by filtration. This left methyl 2-bromo-8-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (484 mg, 1.45 mmol, 58% yield) as a grey solid. MS (ESI) m/z 334.91 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.25 (1H, s), 10.12 (1H, s), 8.80 (1H, s), 8.11 (1H, d, J=9.32 Hz), 7.98 (1H, s), 7.88(1H, d, J=8.56 Hz), 3.33 (3H, s).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[C:13]=2[CH2:12]1)(=[O:10])=[O:9].Br[CH2:31][CH2:32][CH2:33][OH:34].CO>CN(C=O)C.O>[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]([CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[C:13]=2[CH2:12]1)(=[O:9])=[O:10]
Reactant: CS(=O)(=O)N1CCc2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2C1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Reaction time: 0.42 h
Yield: 54.6 %

Procedure:
Cs2CO3 (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 mL) and stirred for 25 min. 3-Bromo-1-propanol (8.6 mL, 13.2 9, 94.9 mmol) was added and stirred under N2 at room temperature for 18 h. Water (500 mL) was added to the reaction and stirred for 5 min. The precipitated material was filtered out and washed with water (4×100 mL) and dried in a Freeze Drying System. The crude material (31.0 g) was taken up in anhydrous DMF (65 mL) and Cs2CO3 (33.74 9, 103.5 mmol) was added, and stirred for 10 min. 3-Bromo-1-propanol (8.6 mL, 13.2 g, 94.9 mmol) and MeOH (6.0 mL, 4.75 9, 148 mmol) were added and stirring continued under N2 at room temperature for 15 h. Water (500 mL) was added to the reaction and stirred for 10 min. The precipitated material was filtered and washed with water (3×100 mL). The filter cake was dissolved in CH2Cl2 (200 mL) and washed with brine (50 mL), dried (Na2SO4), and concentrated. The solid was triturated with Et2O (200 mL), filtered, washed with Et2O, and dried to furnish 16.0 q of the desired compound. The mother liquor was chromatographed (silica, 0-10% acetone/EtOAc) to obtain an additional 3.0 g of the title compound. The combined yield was 54.6%. MS (electrospray): calculated for C17H20F3N3O3S, 403.12; m/z found, 404.0 [M+H]+, 426.0 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.71 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 4.23 (t, J=6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J=5.1 Hz, 2H), 2.62 (t, J=5.9 Hz, 1H), 2.06 (q, J=6.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([C:16]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:34])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.7 %

Procedure:
A solution of Boc-D-phenylglycine (15.0 g, 59.7 mmole) and proline benzyl ester hydrochloride (14.43 g, 59.7 mmole) in 60 ml of DMF was cooled to 0° C. and N,N-diisopropylethylamine (10.3 ml, 59.7 mmole) was added followed by 1-hydroxybenzotriazole hydrate (8.1 g, 59.7 mmole) and DCC (12.3 g, 59.7 mmole). The reaction mixture was stirred for 3 days at room temperature after which it was filtered and the filtrate was evaporated to an oil under vacuum. The oil was dissolved in 200 ml of ethyl acetate and 150 ml of water and after shaking the organic layer was separated, washed three times with 100 ml portions of 0.1N HCl, once with 150 ml of water, three times with 100 ml portion of 5% sodium bicarbonate and again with 150 ml of water. The washed organic solution was dried over MgSO4 and then was evaporated under vacuum to provide 24.8 g of Boc-D-Phg-Pro-OBzl as a solid (95% of theory): TLC Rf (A) 0.75; FAB-MS 439 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[CH:7]=1
Reactant: COCCN
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (2 g, 14 mmol) in iPrOH (70 mL) and DIPEA (1.94 g, 15 mmol) was added a solution of 2-methoxy-ethylamine (1.13 g, 15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.95 g, yield: 82%). MS (ESI): 188 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([P:12]([O:17]CC)([O:14]CC)=[O:13])([OH:11])[C:6]([O:8]CC)=[O:7])#[N:2].C[Si](Br)(C)C.O>C(Cl)(Cl)Cl>[C:1]([CH2:3][CH2:4][C:5]([OH:11])([P:12]([OH:14])([OH:17])=[O:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)C(O)(CCC#N)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CCCC(O)(C(=O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.77 g (0.01 mole) of ethyl 4-cyano-2-diethoxyphosphinyl-2-hydroxybutanoate in 30 ml of CHCl3 is treated with 10.7 g (0.07 mole) of trimethylsilyl bromide. The solution is stirred at 50° for about one day. It's cooled to room temperature, and water is added. The mixture is stirred for about 30 minutes. The layers are separated, and the water layer is washed several times with CHCl3. The water layer is evaporated to dryness under vacuum, and the residue is triturated with acetone to convert it to a solid (filter to collect it), which is 4-cyano-2-hydroxy-2-phosphonobutanoic acid.