Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C(O)C.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(N(C)C)cc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 76.2 %

Procedure:
Ethyl 5-bromo-N-(3,4dichlorobenzyl)indole-2-carboxylate (0.3 g), 4-dimethylaminobenzene boronic acid (0.13 g) and tetrakis triphenylphosphine-palladium(0) (20 mg) were dissolved in degassed toluene/ethanol/2M potassium carbonate (2:2:1) under argon and warmed at 80° C. for 16 hours. The reaction was then cooled to room temperature and partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using i-hexane-15% ethyl acetate as eluent to give the desired end product as a pale brown solid (0.25 g, 76%); NMR δ(CDCl3) 1.38 (t, 3H), 2.98 (s, 6H), 4.38 (q, 2H), 5.78 (s, 2H), 6.80-7.80 (m, 11H); M/z (+) 467 (M+), 319, 280, 239.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=S)[CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[N:19][NH2:20])[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: NN
Reactant: Cc1cc(C)nc(NC(=S)c2cnccn2)c1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)nc(NC(=NN)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 g of compound of Example 24 dissolved in 30 ml of ethanol is added 0.6 ml of hydrazine monohydrate and the mixture is left stirring for 30 minutes at room temperature. The reaction medium is then poured into ice-water. It is stirred vigorously for 20 minutes. The mixture is filtered and dried and the residue is recrystallized from isopropyl ether.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:24][C@:25]([CH3:76])([CH2:74][I:75])[C:26](=[O:73])[C@H:27]([CH2:69][CH:70]([CH3:72])[CH3:71])[NH:28][C:29](=[O:68])[C@H:30]([CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[NH:31][C:32](=[O:60])[C@H:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:34][C:35](=[O:55])[C@H:36]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)(=[O:23])[CH2:9][CH2:10][C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12]>C(Cl)Cl>[CH2:61]([C@@H:30]([C:29](=[O:68])[NH:28][C@@H:27]([CH2:69][CH:70]([CH3:72])[CH3:71])[C:26](=[O:73])[C@:25]([CH2:74][I:75])([CH3:76])[O:24][C:8](=[O:23])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH:31][C:32](=[O:60])[C@H:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:34][C:35](=[O:55])[C@H:36]([CH2:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[NH:37][C:38](=[O:46])[CH2:39][N:40]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: COc1ccc(COC(=O)CCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@@](C)(CI)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Referring to FIG. 43, TFA (6 mL) was added dropwise to a solution of compound (4S,7S,10S,13S,15S)-10-benzyl-16-iodo-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-15-yl 4-methoxybenzyl succinate (21, 1.7 g, 1.59 mmol) in DCM (30 mL) at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. TFA was removed under reduced pressure and the residue was dissolved in DCM (50 mL). The resulting mixture was washed with water (40 mL×3) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give product (quantitative without further purification).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].O.[PH2:7]([O-:9])=[O:8].[Na+].[CH2:11]=[CH:12][CH3:13]>[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].O>[CH2:11]([P:7]([OH:9])([CH2:3][CH2:2][C:1]([OH:5])=[O:4])=[O:8])[CH2:12][CH3:13]
Reactant: C=CC(=O)O
Reactant: O=[PH2][O-]
Reactant: C=CC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCP(=O)(O)CCC(=O)O
Yield: 61 %

Procedure:
Using the method of Example 2, 432 g (6 mol) of acrylic acid were first admixed, at from 65 to 80° C. in the presence of 428 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on acrylic acid) with 636 g (6 mol) of sodium hypophosphite monohydrate dissolved in 860 g of water. The resultant reaction mixture was then reacted with propylene in the presence of 428 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on propylene). Appropriate work-up gave 655 g (61% of theory) of 3-(propylhydroxyphosphinyl)propionic acid as colorless solid; chlorine content: <0.1 ppm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([CH3:21])=[C:6]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:8][C:9]=1[O:10]COC.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CO.N1C=CC=CC=1>[CH3:23][S:24]([O:10][C:9]1[CH:8]=[CH:7][C:6]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:5]([CH3:21])[C:4]=1[O:3][CH3:2])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(NC(=O)C(C)(C)C)c(C)c1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: COc1c(OS(C)(=O)=O)ccc(NC(=O)C(C)(C)C)c1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
A 6N aqueous hydrochloric acid solution (0.355 ml, 2.13 mmol) was added dropwise to a solution of N-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide (300 mg, 1.07 mmol) in methanol (3 ml) at room temperature. After 18 hours, the reaction solution was poured into water (30 ml) and extracted with ethyl acetate (30 ml×2), and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The ethyl acetate layer dried was concentrated under reduced pressure, and to a solution of the resulting residue in pyridine (3 ml) was added methanesulfonyl chloride (0.091 ml, 1.17 mmol) at 0° C. The resulting mixture was heated to 60° C. After 2.5 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was poured into water (50 ml) and extracted with ethyl acetate (30 ml×2). The extract solution was dried over anhydrous magnesium sulfate. The extract solution dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenyl methanesulfonate (338 mg, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:60])[C@@H:45]([NH2:59])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[CH:1]([O:4][C:5]([N:7]1[CH:20]([C:21](=[O:23])[NH:59][C@H:45]([C:44]([O:43][CH3:42])=[O:60])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester (120 mg) was coupled with (S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride according to general procedure A to provide (S)-7-((S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (151 mg, LC/MS: m/z 825).
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH:13]1([C:19]#[CH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:19]2[NH:8][C:7]3[C:2]([CH:20]=2)=[CH:3][C:4]([CH3:12])=[CH:5][C:6]=3[N+:9]([O-:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Reactant: C#CC1CCCCC1
Product: Cc1cc([N+](=O)[O-])c2[nH]c(C3CCCCC3)cc2c1
Yield: 62.4 %

Procedure:
6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) and cyclohexylacetylene (0.23 ml, 1.8 mmol) were reacted according to the same procedure as Preparation 19 to give the title compound (290 mg, Yield 62%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[Br:8][CH2:9][C:10]([OH:12])=[O:11]>CCO>[BrH:8].[Cl:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(O)CBr
Solvent: CCO
Product: Br
Product: N=c1sc(Cl)cn1CC(=O)O
Yield: 9.5 %

Procedure:
At room temperature, 5-chloro-1,3-thiazol-2-amine x170 (1.49 g, 11.03 mmol, 1 eq) is added to a well stirred solution of bromoacetic acid (1.68 g, 11.03 mmol, 1 eq) in EtOH (50 ml). The mixture is heated at reflux during 8 hours. After cooling, the resulting precipitate is filtrated dried under vacuum to yield 288 mg of (5-chloro-2-imino-1,3-thiazol-3(2H)-yl)acetic acid hydrobromide x171 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12](SC)[S:13][C:9]=2[C:8](=[O:16])[N:7]=[CH:6]1.O[O:23][S:24]([O-:26])=O.[K+].[CH2:28]1COCC1>O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([S:24]([CH3:28])(=[O:26])=[O:23])[S:13][C:9]=2[C:8](=[O:16])[N:7]=[CH:6]1
Reactant: CSc1nc2c(s1)c(=O)ncn2Cc1cccc(Cl)c1Cl
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nc2c(s1)c(=O)ncn2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
To a solution of 4-(2,3-dichlorobenzyl)-2-(methylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one (660 mg, 1.842 mmol) in THF (150 mL) and water (60 mL) at 0-5° C. was added Oxone (6.8 g, 11.05 mmol). The resulting mixture was stirred at ambient temperature for 60 hours. After removing THF under reduced pressure, the precipitate formed was collected by filtration and the precipitate was further washed with water, ether and dried in vacuo to give the desired product as a white solid (574 mg, 80%). The compound was directly used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.53 (br, 1H), 7.54 (dd, J=7.8, 1.5 Hz, 1H), 7.35˜7.24 (m, 2H), 5.61 (s, 2H), 3.33 (s, 3H); LC-MS: 390 (MH+); IR (thin film): 3027, 3008, 2925, 1649, 1602, 1488, 1461, 1424, 1405, 1335 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][CH:18]([CH2:23][CH3:24])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[CH:18]([CH2:23][CH3:24])[C:19]([OH:21])([CH3:22])[CH3:20]
Reactant: CCC(N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.163 g, 0.647 mmol), 3-amino-2-methylpentan-2-ol (0.091 g, 0.776 mmol), and K2CO3 (0.179 g, 1.294 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2. After 18 h, the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-chloro-1-(2-hydroxy-2-methylpentan-3-yl)-1H-indole-5-carbonitrile (0.0761 g, 43% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=2.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 4.07 (dd, J=11.6, 3.6 Hz, 1H), 2.09 (m, J=3.6 Hz, 2H), 1.44 (s, 1H), 1.35 (s, 3H), 1.08 (s, 3H), 0.65 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 277 ([M+H]+, 70%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C)cccc2Cl)C1=S
Yield: 40.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.2 g), 2-chloro-6-methylphenyl-isothiocyanate (9.1 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3.5 hours. The solvent was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (5.4 g) as a creamy solid, m.p. 124°-126° C. Anal. Calcd. for. C12H13Cl N2 O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=C(NCCCN2CCC(C#N)C2)N=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=[O:42]>C(Cl)Cl.N>[N+:17]([C:22]1[CH:23]=[C:24]2[C:28]([CH2:27][CH2:26][CH2:25]2)=[CH:29][C:21]=1[NH:20][C:10](=[O:11])[CH3:12])([O-:16])=[O:42]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.67 mL, ca. 13.3 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 56 (449 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 56 (198 mg, 44%) and (ii) 1,4-dioxide 57 (70 mg, 15%) as a red gum: 1H NMR δ 8.15 (br t, J=5.3 Hz, 1H, NH), 8.12 (s, 1H, H-9), 8.08 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.15-3.23 (m, 2H, CH2N), 3.11 (br t, J=7.5 Hz, 2H, H-6), 3.07 (br t, J=7.5 Hz, 2H, H-8), 2.90-2.95 (m, 1H, CHCN), 2.73 (t, J=6.3 Hz, 2H, CH2N), 2.50-2.61 (m, 2H, CH2N), 2.33-2.43 (m, 1H, CH2), 2.11-2.24 (m, 3H, CH2, H-7), 1.91 (p, J=6.3 Hz, 2H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.6, 122.0, 115.8, 111.5, 57.3, 53.5, 52.8, 41.0, 33.4, 32.3, 29.1, 26.9, 26.1, 25.3; MS (FAB+) m/z 355 (MH+, 30%), 339 (10); HRMS (FAB+) calcd for C18H23N6O2 (MH+) m/z 355.1883, found 355.1893.
Reaction SMILES: [C:1]([OH:7])(C(F)(F)F)=[O:2].O=C(C[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C(OCC)=O.C([BH3-])#N.[Na+].Br.CC(O)=O.C(OC(C([NH:46][C@H:47]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([OH:62])=[O:61])=[O:57])[CH2:48][CH2:49][CH2:50][NH:51][C:52](=[O:55])[CH2:53][NH2:54])CCC1C=CC=CC=1)=O)C>>[C:1]([NH:54][CH2:53][C:52]([NH:51][CH2:50][CH2:49][CH2:48][C@@H:47]([C:56]([N:58]1[CH2:65][CH2:64][CH2:63][C@H:59]1[C:60]([OH:62])=[O:61])=[O:57])[NH2:46])=[O:55])([O:7][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](CCCNC(=O)CN)C(=O)N1CCC[C@H]1C(=O)O
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: N[C@@H](CCCNC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-[N5 -(N-Cbz-glycyl)-L-ornithyl]-L-proline was prepared as described in Example 4. The reductive alkylation of TFA salt (132 mg, 0.314 mmol) with ethyl 2-oxo-4-phenylbutyrate (324 mg, 1.57 mmol) and sodium cyanoborohydride (59.2 mg, 0.942 mmol) was carried out in the usual manner. The work up, including 30-32% HBr/HOAc treatment, was the same as that described in Example 1. Both ms and nmr were consistent with the structure for N-[N2 -(1-ethoxycarbonyl-3-phenylpropyl)-N5 -glycyl-L-ornithyl]-L-proline (47.5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][O:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.BrC1C=CC2C3N(CCCOC(C)C)C(COCC)=NC=3C=[N:31]C=2C=1.[O:48]1[CH2:52][CH2:51][NH:50][C:49]1=[O:53].N1CCCC1=O>>[NH2:31][C:8]1[C:7]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[C:5]2[N:4]=[CH:3][C:2]([N:50]3[CH2:51][CH2:52][O:48][C:49]3=[O:53])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: O=C1NCCO1
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)C
Agent: O=C1CCCN1
Product: CCOCc1nc2c(N)nc3cc(N4CCOC4=O)cnc3c2n1CC(C)C

Procedure:
The general methods described in Parts A and B of Example 2 were followed using 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in lieu of 7-bromo-2-(ethoxymethyl)-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline and 2-oxazolidinone in lieu of 2-pyrrolidinone. The product, 3-[4-amino-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-7-yl]-1,3-oxazolidin-2-one (0.125 g) was isolated as an white solid with yellow tinge, m.p. 174-176.5° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][NH:21][C@H:22]1[CH2:27][NH:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:20][N:21]1[C:2](=[O:4])[N:26]2[CH2:27][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 125 %

Procedure:
Triphosgene (21.3 g, 72 mmol) was added in portions to a solution of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL) at 0° C. After stirring at 20° C. overnight, the reaction mixture was washed with H3PO4 (10%), sat. NaHCO3 and saturated NaCl. The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50%) as a yellow solid. 1H NMR (400 Mz, CDCl3): δ 7.43-7.36 (m, 5H), 5.06 (d, J=11.4 Hz, 1H), 4.90 (d, J=11.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.32-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.93 (d, J=11.9 Hz, 1H), 2.14-2.05 (m, 2H), 2.05-2.00 (m, 1H), 1.71-1.63 (m, 1H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[NH:10][C:8]1=[O:9].C(N1C2C(=O)N(CCCC[C@@H](O)C)C(=O)N(C)C=2N=C1)C1C=CC=CC=1.C(N1C2C(=O)N(CCCC[C@H](O)C)C(=O)N(C)C=2N=C1)C1C=CC=CC=1>>[OH:1][C@@H:2]([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH3:18])[CH:13]=[N:12][C:11]=2[NH:10][C:8]1=[O:9]
Reactant: C[C@@H](O)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O
Agent: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Product: C[C@H](O)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O

Procedure:
(S)-1-(5-hydroxyhexyl)-7-methylxanthine was synthesized from (R)-1-(5-hydroxyhexyl)-7-methylxanthine according to the method described in Example 30 for the synthesis of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine from (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:12])[CH2:10]Br)=[CH:4][C:3]=1[Cl:13].[O:14]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][N:31]([CH2:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[OH:12])=[CH:4][C:3]=1[Cl:13]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1Cl
Reactant: c1ccc(CNCCCOCCOCCCOc2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCOCCOCCCOc2ccccc2)Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
1-[4-Amino-3,5-dichlorophenyl]-2-bromoethanone (0.95 g), N-[3-[2-(3-phenoxypropoxy)ethoxy]propyl]benzenemethanamine (1.15 g) and DEA (0.48 g) were stirred together in THF (35 ml) at room temperature under nitrogen for 7 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (35 ml) and treated portionwise with sodium borohydride (0.34 g), at 0° C. under nitrogen, stirred at room temperature for 18 h, diluted with water (150 ml) and the solvent evaporated in vacuo. The residue was extracted with ethyl acetate (2×150 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System H (95:5:1) gave the title compound (1.30 g) as an oil. T.l.c. (System H 90:10:1) Rf 0.39