Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH:17]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])[N:16]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:15]3[S:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH:17]([C:18]([OH:20])=[O:19])[N:16]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:15]3[S:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(Cc4ccccc4)CC3)S[C@H]12
Agent: [Pd]
Solvent: CCO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C3(CCN(Cc4ccccc4)CC3)S[C@H]12
Yield: 71 %

Procedure:
Under a hydrogen pressure of 3.2 kg/cm2 and in the presence of 4 g of palladium on carbon (10% Pd), a solution of benzyl 1'-benzyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylate (prepared in I.2.a) in 800 ml of ethanol is hydrogenolyzed in a Parr's apparatus for 1,5 hours, then filtered and the filtrate is evaporated to dryness in a vacuum and the residue is triturated in isopropyl alcohol. 1'-Benzyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylic acid is thus obtained in a yield of 71%; M.P. 170°-171° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][C:15]=2[C:28]#[N:29])=[CH:11][CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[C:28]([C:15]1[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:30]=[CH:31][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[CH:10][CH:11]=1)#[N:29]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3c(Cl)cccc3Cl)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2c(Cl)cccc2Cl)cc1
Reaction time: 0.75 h
Yield: 111.5 %

Procedure:
tert-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.034 g).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]>CO.[Pd]>[NH2:1][C:2]([C@:4]1([CH3:30])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@@]1(C)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-2-methyl-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D9, 850 mg, 2.07 mmol) in methanol (10 ml) was added Pd/C 10% wt (85 mg, 10 wt %) and the mixture was stirred under hydrogen (1 atmosphere) for 5 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (D10, 623 mg, 94%); Rt (HPLC): 4.00 min; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.16 (s, 1H), 7.28-7.42 (m, 1H), 7.16-7.26 (m, 2H), 7.02-7.14 (m, 1H), 6.59-6.68 (m, 2H), 4.56-4.85 (m, 1H), 2.07-2.41 (m, 2H), 1.52-1.77 (m, 2H), 1.51 (s, 3H), 1.31 and 1.05 (s, s, 9H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[Cl:6]([O-])(=[O:8])=[O:7].[Na+:10].[OH:11][OH:12]>>[Cl:6](=[O:8])=[O:7].[O:11]=[O:12].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:10].[Na+:10]
Reactant: OO
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=O
Product: O=S(=O)([O-])[O-]

Procedure:
Referring to the FIGURE, sulfuric acid and a pre-mixed aqueous solution of sodium chlorate and hydrogen peroxide are fed to a vertical through-flow tubular reactor 1 and reacted therein to form a product stream 2 of liquid and foam comprising chlorine dioxide, oxygen, sodium sulfate and some remaining sulfuric acid and sodium chlorate. An eductor 3 is supplied with motive water 4 and generates a slightly subatmospheric pressure bringing the product stream out from the reactor 1 into the eductor 3 where it is mixed with the motive water to form a diluted product stream 5, which is brought to a tank 6. A part of the diluted product stream is withdrawn from the tank by a pump 8 as a final product 9, i.e. an aqueous solution comprising chlorine dioxide. The tank 6 is provided with a fan 7 venting out oxygen that goes off from the diluted product stream therein. The non-withdrawn part of the diluted product solution is brought out from the tank 6 by the pump 10 and mixed with cold water 11, e.g. having a temperature from about 1 to about 20° C., preferably from about 4 to about 10° C., to form a recycle stream 12. The gas vented out from the tank 6 may also contain some chlorine dioxide and to minimize the losses thereof it is possible to scrub the gas with water to absorb most of the chlorine dioxide (not shown in the FIGURE) and return it to the diluted product stream or the recycle stream. The recycle stream 12 is returned to the eductor and fed thereto as motive water 4. In a process producing a 6 grams ClO2/litre product solution 9 it may be suitable to add enough water to obtain a recycle stream 12 comprising from about 3 to about 4.5 grams ClO2 per litre, depending on how efficient the eductor is. In order to produce a 10 grams ClO2/litre product solution 9 it may be suitable to add enough water to obtain a recycle stream 12 comprising about 7 grams ClO2 per litre.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccccc1F)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-(3-(4-bromophenyl)-3-(2-fluorophenyl)propanoyl)-pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=414.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.O>CS(C)=O>[O:20]1[CH2:4][CH:19]1[CH:16]1[CH2:17][CH2:18][C:13]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:14][CH2:15]1
Reactant: C[S+](C)(C)=O
Reactant: O=CC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C1COC2(CCC(C3CO3)CC2)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 60% strength dispersion of sodium hydride in mineral oil (1.78 g, 44.59 mmol) was taken up in dimethylsulfoxide (25 ml), and trimethylsulfoxonium iodide (9.80 g, 44.6 mmol) was added. The mixture was stirred at room temperature for 45 min. A solution of 1,4-dioxaspiro[4,5]decane-8-carbaldehyde (7.59 g, 44.6 mmol) in dimethylsulfoxide (20 ml) was then added to the mixture. The reaction mixture was stirred at 60° C. for 18 h. After cooling, the mixture was poured into water (100 ml) and extracted with diethyl ether (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The crude product (4.64 g) was purified by flash chromatography with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:9][C:8]2=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]1[O:12][CH2:11][CH:10]([C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:9][C:8]2=1)[CH3:2]
Reactant: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](C4COc5cnc6ccc(O)cc6c5C4)CC3)cc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl iodide (6 μL, 0.07 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(6-hydroxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-amide (40 mg, 0.07 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by sodium hydride (55% purity, 3.2 mg, 0.07 mmol, 1.0 eq). After 2 hours stirring at room temperature, 1.0 additional equivalent of ethyl idodide and sodium hydride are added to the reaction mixture that is stirred at room temperature for one hour. Then solvent is evaporated and the crude is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [trans-4-(6-ethoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-amide as an off-white lyophilizated powder (11 mg, 27% yield).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH2:13][OH:14]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[O:5][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: OCCCCO
Reactant: CCP(=O)(O)CCC#N
Solvent: Cc1ccccc1
Product: CCP(=O)(CCC#N)OCCCCO
Yield: 91.8 %

Procedure:
441 g (3.0 mol) of ethyl-2-cyanoethylphosphinic acid (produced as in Example 5) are at 80° C. dissolved in 400 ml of toluene and admixed with 315 g (3.5 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene and excess ethyl glycol is removed in vacuo to leave 604 g (92% of theory) of 4-hydroxybutyl ethyl(2-cyanoethyl)phosphinate as colorless oil.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([NH2:26])[C:15](=[O:27])[N:14]1[CH:10]([CH2:11][CH:12]([O:28][C:29]([N:31]3[CH2:40][CH2:39][C:38]4[C:33](=[C:34](C(F)(F)F)[CH:35]=[CH:36][CH:37]=4)[CH2:32]3)=[O:30])[CH2:13]1)[C:9](=[O:45])[NH:8]2)=[O:6])C.C(N(C(C)C)CC)(C)C.[CH:55]1([N:60]=[C:61]=[O:62])[CH2:59][CH2:58][CH2:57][CH2:56]1>ClCCl>[CH:55]1([NH:60][C:61](=[O:62])[NH:26][C@@H:16]2[C:15](=[O:27])[N:14]3[C@@H:10]([CH2:11][C@@H:12]([O:28][C:29]([N:31]4[CH2:40][CH2:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:32]4)=[O:30])[CH2:13]3)[C:9](=[O:45])[NH:8][C@@:7]3([C:5]([OH:4])=[O:6])[C@@H:24]([CH2:25]3)[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: O=C=NC1CCCC1
Reactant: CCOC(=O)C12CC1C=CCCCCCC(N)C(=O)N1CC(OC(=O)N3CCc4cccc(C(F)(F)F)c4C3)CC1C(=O)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCC1)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3CCc4ccccc4C3)CN2C1=O
Reaction time: 1 h
Yield: 89.3 %

Procedure:
14-Amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester hydrochloride salt (49 mg, 74 umol), diisopropylethylamine (29 mg, 222 umol), and cyclopentyl isocyanate (25 mg, 222 umol) were taken up in 375 uL dichloromethane and stirred at 19 C for 1 hour. The reaction was loaded directly onto a C18 flash column and eluted with water/acetonitrile (10 to 100%) containing 0.1% TFA to provide the title product as a white solid (42 mg, 77%). MS m/z 732.2 (MH+).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[C:15]([S:19]([NH2:21])=[O:20])([CH3:18])([CH3:17])[CH3:16]>[O-]CC.[Ti+5].[O-]CC.[O-]CC.[O-]CC.[O-]CC.C1COCC1>[CH3:16][C:15]([S:19](/[N:21]=[CH:11]/[C:10]1[CH:13]=[CH:14][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1)=[O:20])([CH3:18])[CH3:17]
Reactant: CCCS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+5]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Propylsulphonyl)benzaldehyde (1.81 g, 8.53 mmol, prepared as described in Example 47a, tert-butyl sulphinamide (1.55 g, 12.8 mmol), titanium(V) ethoxide (3.58 mL, 17.1 mmol) and THF (50 mL) were heated at reflux for 3 h then stirred at room temperature overnight. The reaction mixture was quenched with water (200 mL) before addition of ethyl acetate (200 mL). Celite was added and the mixture stirred for 15 min before being filtered. The phases were separated and the organic extract dried (MgSO4) and concentrated. The yield of the title compound was assumed to be quantitative and the material was used without further purification. m/z (ES+) 316 (M+H).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1([CH3:41])[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:10]1[C:16]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[C:25]([NH2+:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:21][N:22]=1)=[O:17].[BH4-].[Na+]>CO>[OH:17][CH:16]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:21][N:22]=1)[CH:10]1[CH2:11][CH2:12][CH:13]([OH:15])[CH2:14][C:9]1([CH3:8])[CH3:41]
Reactant: Cc1cc([NH2+]c2nccc(C(F)(F)F)n2)cc(-c2cnc(C(=O)C3CCC(=O)CC3(C)C)s2)c1
Agent: O=C([O-])C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C3CCC(O)CC3(C)C)s2)c1
Temperature: 0 °C

Procedure:
N-(3-{2-[(2,2-Dimethyl-4-oxocyclohexyl)carbonyl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-aminium trifluoroacetate (100 mg, 0.166 mmol) was dissolved in methanol (1.66 mL) and cooled to 0° C. Sodium borohydride (18.8 mg, 0.498 mmol) was added to the reaction, and the resultant mixture was aged at 0° C. for 30 minutes. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were concentrated in vacuo and purified via silica gel column chromatography to provide 4-{hydroxy[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-3,3-dimethylcyclohexanol. MS ESI calc'd. for C24H28F3N4O2S [M+H]+ 493. found 493. Mixture present as a ˜4:1 mixture of diastereomers. 1H NMR data reported as the observed integrals for each peak. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=4.9, 1H), 7.77 (m, 2H), 7.62 (m, 1H), 7.28 (m, 1H), 7.04-7.00 (m, 2H), 5.07 (d, J=7.2, 0.8H), 4.94 (d, J=7.2, 0.2H), 3.98-3.91 (m, 0.8H), 3.72-3.64 (m, 0.2H), 2.34 (m, 3H), 1.77-1.20 (m, 6H), 1.21 (s, 0.6H), 1.16 (s, 2.4H), 1.12 (s, 2.4H), 0.95 (s, 0.6H). rhSyk activity=+++.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3]C(C)(C)C)=O.[CH2:17]([NH:24][CH2:25]C(OCC)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:17]([N:24]1[CH2:25][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:14]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Yield: 102 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-norleucine (10.5 g, 45.2 mmol), ethyl N-benzylglycinate (8.72 g, 45.2 mmol) and dicyclohexylcarbodiimide (9.33 g, 45.2 mmol). The crude diketopiperazine was triturated with hexane to give the title compound as a white powder (12.0 g). NMR (300 MHz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H, br s), 4.07 (1H, dt, J=3, 6 Hz), 3.87 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[C:27]([CH2:28]Cl)=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].C(O)C(N)(CO)CO>ClCCl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[C:27]([CH2:28][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:37](=[O:39])[CH3:38])=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: Nc1ccccc1S
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1SCc1cc2c(cc1Cl)OCO2
Reaction time: 0.17 h

Procedure:
2-aminothiophenol (0.4 mmol) and PS-DIEA resin (0.35 g, 3.76 mmol/g) were combined in dichloromethane (4 mL) and agitated for 10 min. 5-chloro-6-(chloromethyl)-1,3-benzodioxole (0.3 mmol) was added and the reaction agitated for a further 3 h. Reaction was treated with MP BH4− resin (Argonaut 3.16 mmol/g) for 2 h then filtered. The filtrate was combined with triethylamine (0.4 mmol), PS-DMAP resin (0.1 g) and acetyl chloride (0.4 mmol). Agitate for 18 h then treat the reaction with PS-trisamine resin for 4 h, filter and remove the solvent under a stream of nitrogen. The residue was purified by reverse phase chromatography. 1H NMR (CDCl3) δ 8.38-8.32 (m, 2 H), 7.52 (m, 1 H), 7.38-7.32 (m, 1 H), 7.07-7.02 (m, 1 H), 6.83 (s, 1 H), 6.25 (s, 1 H), 5.93 (s, 2 H), 3.90 (s, 2 H), 2.09 (s, 3 H);MS (ESI+) for C16H14ClNO3S m/z 336 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:13][CH:10]1[CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1Br
Reactant: NC1CC1
Product: Brc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-bromobenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 47.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.075 g, 0.149 mmol) obtained in step 2 and methanesulfonamide (0.070 g, 0.745 mmol), the title compound (0.041 g, 47%) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([C:36](=[O:38])[NH2:37])=[CH:31][C:30]=1[CH3:39])[C:9](=[O:27])[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH:8]([C:9](=[O:27])[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1)[CH2:28][C:29]1[C:30]([CH3:39])=[CH:31][C:32]([C:36]([NH2:37])=[O:38])=[CH:33][C:34]=1[CH3:35]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C

Procedure:
To {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (0.60 g, 1.10 mmol) was added 0° C. trifluoroactic acid (4 mL). The resulting solution was warmed to room temperature, and after 30 minutes the excess trifluoroacetic acid was removed under a stream of nitrogen. This material was purified via a Gilson preparative HPLC resulting in the isolation of desired product 4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-benzamide as a white solid after lyophilization, which proved 100% pure by HPLC at 254 and 214 nm, (LC/MS; Measured MW (MH+): 446).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:35][CH2:34]1
Reactant: O=C1CCC(CO)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(CO)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[NH:13][N:12]=2)=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[NH:13][N:12]=2)=[C:6]([NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCc1cc([N+](=O)[O-])[nH]n1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)n[nH]1
Yield: 70.5 %

Procedure:
Following General Procedure B, the title compound (580 mg, 71%) was prepared from 5-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline (503 mg, 1.77 mmol) and benzofuran-2-sulfonyl chloride (384 mg, 1.77 mmol) in pyridine (5 ml).