Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6](=[O:22])[CH:7]([O:19][CH2:20][CH3:21])[N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[C:27]([C:25]1[CH:24]=[CH:23][C:3]([CH2:4][NH:5][C:6](=[O:22])[CH:7]([O:19][CH2:20][CH3:21])[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:17])[C:9]2=[O:18])=[C:2]([NH:1][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])[CH:26]=1)#[N:28]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1N)N1Cc2c(C)cccc2C1=O
Reactant: O=Cc1ccccc1F
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1NCc1ccccc1F)N1Cc2c(C)cccc2C1=O
Reaction time: 16 h
Yield: 85.5 %

Procedure:
(RS)-N-(2-Amino-4-cyano-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.101 g) was treated in MeOH (2 ml) successively with 2-fluoro-benzaldehyde (99 mg) and 1 ml of a MeOH-solution containing scrupulously dried ZnCl2 (145 mg) and NaCNBH3 (50 mg). The reaction mixture was stirred for 16 h at 50–55° C., poured onto crashed ice and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt=1/1) to give (RS)-N-[4-cyano-2-(2-fluoro-benzylamino)-benzyl]-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (111 mg) as colorless oil, MS 487.4 ([M+H]+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([CH3:39])[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=3)[N:9]=2)=[C:32]([CH3:39])[CH:31]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.41 mmol) in dioxane (5.0 mL) and water (3 drops) was added (4-fluoro-2-methylphenyl)boronic acid (101 mg, 0.66 mmol), Pd(PPh3)4 (19.0 mg, 0.02 mmol), and K3PO4 (138.3 mg, 0.65 mmol). The reaction was stirred for 1 hour at 90° C. under a nitrogen atmosphere. The resulting solution was concentrated in vacuo, and then purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to provide (S)-methyl 2-(4-fluoro-2-methylphenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (120 mg, 78%).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>CO.C(OCC)(=O)C>[CH:17]1([CH2:16][N:13]2[C:12]3[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([C:22]([F:24])([F:25])[F:23])[C:11]=3[N:15]=[N:14]2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Benzyloxy-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (5.04 g, 14.5 mmol) was dissolved in 1:1 mixture of methanol/ethyl acetate (40 mL). The mixture was sparged under nitrogen, treated with Pearlman's catalyst (2 g, 0.2 wt equiv) and then sparged under hydrogen (1 atm) and stirred vigorously for 90 minutes. The mixture was filtered through a pad of Celite, which was washed with methanol (500 mL) and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([C@:3]1([C:14]([O:16]C)=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1)[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:20]=1[O:31][CH2:32][CH2:33][CH2:34]Br>>[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:22]=[CH:21][C:20]=1[O:31][CH2:32][CH2:33][CH2:34][O:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][C@:3]([CH2:1][CH3:2])([C:14]([OH:16])=[O:15])[O:4]2)=[CH:9][CH:8]=1
Reactant: Clc1cc(C2CCOCC2)ccc1OCCCBr
Reactant: CC[C@]1(C(=O)OC)CCc2ccc(O)cc2O1
Product: CC[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCOCC4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 5, Steps D-E employing (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxylate (Example 13, Step E) instead of ethyl 7-hydroxychromane-2-carboxylate, and 3-bromopropyl 2-chloro-4-(4-tetrahydropyranyl)phenyl ether instead of 3-bromopropyl 2-chloro-4-(2,2,2-trifluoroethoxy)phenyl ether.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([CH2:13][C:4]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccncc1
Reaction time: 2 h
Yield: 10.1 %

Procedure:
To a solution of N-methoxy-N-methylisonicotinamide (500 mg, 3.0 mmol) in anhydrous THF (10 mL) was added benzylmagnesium chloride (2 M in THF, 1.8 mL, 3.6 mmol) drop wise at −78° C. After being stirred at the temperature for 2 h, the reaction was quenched with NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=5:1) to give Intermediate 35 (60 mg, yield 10%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH2:5]([N+:7]1[CH:11]=[CH:10][N:9]([CH2:12]C)[CH:8]=1)[CH3:6].[C:14]([O-])(=O)CCCCCCC.C([N+]1C=CN(CC)C=1)C.CCCCCCCCCCCC(O[Sn](OC(CCCCCCCCCCC)=O)(CCCC)CCCC)=O>>[C:1]([O-:4])(=[O:3])[CH3:2].[CH2:5]([N+:7]1[CH:11]=[CH:10][N:9]([CH3:12])[C:8]=1[CH3:14])[CH3:6]
Reactant: CCCCCCCC(=O)[O-]
Reactant: CCn1cc[n+](CC)c1
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC
Product: CC[n+]1ccn(C)c1C

Procedure:
1,3-diethylimidazolium acetate and 1,3-diethylimidazolium octanoate are better relative to DBTL as reference, in terms of drying and the early development of pendulum hardness.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([C@@:18]2([CH3:20])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:22][CH2:23]1)=[NH:28]
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: NO
Agent: Cl
Product: C[C@@]1(C2CCN(C(=N)NO)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 42; the configuration of the stereocenter is arbitrarily assigned) and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 4): tR=0.46 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][C@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][N:26]=[N+:27]=[N-:28])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 85A from 200 mg (0.52 mmol) of (2S)-2,4-bis[(tert-butoxycarbonyl)amino]butyl methanesulfonate (Example 90A) in 15 ml of dimethylformamide with 34 mg (0.52 mmol) of sodium azide. The product is reacted without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:7]1([C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O[C@@H]1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
(R)-(+)-3-Pyrrolidinol (1.0 g, 11.5 mmol) (Aldrich) and triphenylchloromethane (1.00 g, 3.59 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 3 hours. The mixture was allowed to cool to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.73 g, 62% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([Cl:2])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: CSc1ccc(NNC(=O)c2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: CSc1ccc(NN=C(Cl)c2ccccc2)cc1

Procedure:
A mixture consisting of 7.9 g. (0.038 mole) phosphorus pentachloride, 100 ml. carbon tetrachloride, and 9.05 g. (0.035 mole) benzoic acid 2-[p-(methylthio)phenyl]hydrazide (prepared in Part A above) was heated at the reflux temperature until evolution of gas ceased. The reaction mixture was chilled in ice, and a suspension of 11.3 g. (0.12 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation under reduced pressure, the resulting triphenylphosphate solution of the desired product was poured through a column of silica gel. The column was eluted with a mixture of 1 part benzene and 1 part Skellysolve B. After removing the solvents from the eluate by evaporation under reduced pressure, the residue was recrystallized two times from cyclohexane to give benzoyl chloride [p-(methylthio)phenyl]hydrazone having a melting point at 94° to 95° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:21][C:10]1[C:11]([O:12][CH3:13])=[C:2]([CH3:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2ncccc2cc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C)cc2cccnc2c1Br
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 6-methyl-7-methoxy-quinoline (3.0 g, 17.3 mmol) in DMF (20 ml) was added NBS (3.4 g, 19 mmol). The resulting suspension was stirred for 3 h at 60° C. and monitored by LCMS. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and then purified by flash column chromatography on silica gel to give the desired product (2.9 g, 67%). MS (ES) m/z 251.6 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1.[C:24]([Li])(C)(C)C.CCCCC.IC.C([O-])(=O)C.[NH4+]>C1COCC1.C(Cl)Cl>[CH3:24][C:2]1[C:3]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[C:6]=2[CH:16]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)C(=O)Nc1cc2c(cc1Br)S(=O)(=O)c1ccccc1-2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: Cc1cc2c(cc1NC(=O)C(C)(C)C)-c1ccccc1S2(=O)=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-5,5-dioxo-2-pivaloylaminodibenzothiophene (Example 70; 0.1 g, 0.254 mmol) was suspended in dry THF (2 ml) under argon, cooled to −70° C. and 1.7 M tert-butyllithium in pentane (0.49 ml, 0.838 mmol) was added dropwise over 5 minutes. The mixture was allowed to warm to −30° C. and the suspension slowly dissolved as the solution darkened. The mixture was then re-cooled to −70° C. and iodomethane (0.17 ml, 0.279 mmol) added and stirred for 30 minutes. Saturated ammonium acetate (5 ml) and DCM (25 ml) were added and the organic phase washed with water and dried. The mixture was evaporated in vacuo and the residue purified by preparative HPLC (Dynamax C-18 60A column eluted with 30-90% acetonitrile in water plus 0.1% trifluoroacetic acid) to give the product as a colourless solid. NMR: 9.16 (s, 1H), 8.13 (d, 1H), 7.99 (s, 1H), 7.92 (d, 1H), 7.86 (s, 1H), 7.76 (t, 1H), 7.61 (t, 1H), 2.28 (s, 3H), 1.26 (s, 9H); m/z 330.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH3:13])[CH2:10][CH2:11][SH:12].[NH2:14][C:15]1[N:23]=[C:22](Cl)[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Na+].O>[NH2:14][C:15]1[N:23]=[C:22]([S:12][CH2:11][CH2:10][CH:9]([CH3:13])[CH3:8])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 47.6 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 3-methylbutane-1-thiol (1 ml, 8.0 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 2.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (120 mg, yield 48%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O.C1COCC1>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(N)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)Oc2ccccc2)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reaction time: 5 h

Procedure:
0.24 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.05 g of the compound obtained in Example 7 in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1.35 g of the expected product were obtained by crystallization from iso ether. M.p.=236° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([F:19])=[CH:8][C:9]([Cl:18])=[C:10]([NH:12][S:13]([CH2:16][Cl:17])(=[O:15])=[O:14])[CH:11]=1>C1(C)C=CC=CC=1>[Cl:17][CH2:16][S:13]([NH:12][C:10]1[CH:11]=[C:6]([N:5]=[C:1]=[O:2])[C:7]([F:19])=[CH:8][C:9]=1[Cl:18])(=[O:15])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirred solution of phosgene (68 mmol) in 35 mL toluene was added the title compound of Step D (4.2 g, 15.4 mmol) in 80 mL toluene at 0° C. and the reaction was stirred at room temperature overnight. The temperature was then raised to 70° C. for 4 h. After cooling to room temperature, the reaction mixture was filtrated and the solvent was removed under reduced pressure. Drying of the white precipitate under reduced pressure yielded the title compound of Step E (4.4 g, 95%) melting at 101.5-102.5° C. 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.3 (d, 1H), 7.0-6.9 (br s, 1H), 4.64.5 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@H](Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, 1.21 mmol, 1 equiv), (R)-methyl 2-bromo-2-phenylacetate (276.6 mg, 1.21 mmol, 1 equiv) and potassium carbonate (418.1 mg, 3.025 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient—2%-20% ethyl acetate/hexanes,) to afford (R)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (410 mg, 71.1%); MS for C27H33N3O5 m/z 479.57 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C:25]([OH:27])=[O:26])[CH2:10][CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].C(CON1[C:41](=[O:42])[CH:40]=[CH:39][C:38]1=[O:43])(O)=O>C(=O)(O)[O-].[Na+]>[C:38]1(=[O:43])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:21][CH2:22][N:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:28][C:29]([OH:31])=[O:30])[CH2:10][CH2:11][N:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:17][C:18]([OH:20])=[O:19])[C:41](=[O:42])[CH:40]=[CH:39]1
Reactant: NCCCCCCCN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reactant: O=C(O)CON1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CN(CCN(CCCCCCCN1C(=O)C=CC1=O)CCN(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
A solution of [((7-aminoheptyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.72g, 1.6 mmol) in saturated aqueous sodium bicarbonate (15 ml) was cooled in an ice bath and N-carboxymethoxymaleimide (prepared according to Helv. Chim. Acta, 58, 531 [1975]) (0.25 g, 1.6 mmol) was added in one portion. After stirring 20 minutes the ice bath was removed and stirring was continued for 30 minutes. The solution was brought to ph≈6 with 1N HC1 and concentrated under reduced pressure. The residue was chromatographed on a 2×30 cm column of Bio-Rad AG 1×8 ion exchange resin in the formate form (gradient elution, 0-1M formic acid) to provide 0.61 g of slightly impure product. This material was rechromatographed as above to yield pure [((7-maleimidoheptyl)imino)bis(ethylenenitrilo)]tetraacetic acid (0.42g, 50%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:13]1[CH:18]=[C:17]([S:19][CH3:20])[N:16]=[C:15]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:14]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][S:21][C:15]1[N:14]=[C:13]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:18]=[C:17]([S:19][CH3:20])[N:16]=1
Reactant: CS(N)(=O)=O
Reactant: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CSc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of methane sulfonamide (0.22 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl(XPHOS) (17 mg), cesium carbonate (0.58 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-(methylthio)pyrimidine (the product of step i) (0.38 g) in dioxane (10 mL) was heated at 100° C. for 18 h. The mixture was cooled and saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% TFA mixtures to give the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: [OH:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=O.CO[C:10](OC)([CH3:12])[CH3:11].C(O)[C@H](O)C(O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:11][C:10]1([CH3:12])[O:1][CH:2]([CH2:3][OH:5])[CH2:6][O:7]1
Reactant: O=C(O)C(O)CO
Reactant: COC(C)(C)OC
Agent: O=C(O)[C@@H](O)CO
Agent: [Al+3]
Agent: [H-]
Product: CC1(C)OCC(CO)O1

Procedure:
Alternatively, the 2,3-dihydroxypropanoic acid (D- or L-glyceric acid) is reacted with 2,2-dimethoxypropane without lower alcohol present to prepare 2,3-O-isopropylidene D- or L-glyceric acid which is then reacted with lithium aluminum hydride to produce the solketal.