Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3([N:43]4[CH2:48][CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45][CH2:44]4)[C:39](=[O:40])[NH:38][C:37](=[O:41])[NH:36][C:35]3=[O:42])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3([N:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[C:39](=[O:40])[NH:38][C:37](=[O:41])[NH:36][C:35]3=[O:42])=[CH:32][CH:33]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCN(C(=O)OC(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 199.6 %

Procedure:
The product from example 13 (50 mg, 0.0635 mmol) was treated with trifluoacetic acid (2.0 mL) in dichloromethane (2.0 mL) at rt for 1 h. The mixture was concentrated in vacuo to provide the title barbituric acid (50.8 mg, 100%). MS found: (M+H)+=460.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (63 mg) and pyridine (25 μl) in dichloromethane (0.6 ml) was added dropwise benzoyl chloride (22 μl), and the mixture was stirred at room temperature for more than 2 hours. The mixture was partitioned between chloroform-methanol and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide (80 mg) as a white amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=O.[CH3:13][N:14]=[C:15]=[S:16].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15](=[S:16])[NH:8][N:7]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: NNC(=O)c1cc(F)cc(F)c1
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Temperature: 70 °C

Procedure:
3,5-difluorobenzohydrazide (5 g, 29 mol) and methyl isothiocyanate (2.1 g, 29 mmol) were mixed in 2-propanol (100 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and the formed precipitate was filtered off. H2O (100 mL) and NaHCO3 (4 g, 48 mmol) were added to the solid and the mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 6.4 g (97%), was collected by filtration. LC-MS (M++1): 228
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:62]2[N:63]=[C:64]([NH:67]C(OC(C)(C)C)=O)[S:65][CH:66]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][CH:44]3[CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:67][C:64]1[S:65][CH:66]=[C:62](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][CH2:43][CH:44]3[CH2:47][NH:46][CH2:45]3)[CH:38]=[N:37]2)=[O:24])[N:63]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN(CC3CN(C(=O)OC(C)(C)C)C3)C(=O)OC(C)(C)C)n2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CNCC3CNC3)n2)cs1

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (130 mg, 0.122 mmol), TFA (0.56 mL, 7.32 mmol), and DCM (1.5 mL). 6.3 mg. LCMS: Rt=0.47 min, m/z=599.3 (M+1). Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.82 (s, 1H), 7.10 (s, 1H), 5.61 (d, J=5.9 Hz, 1H), 5.01 (q, J=5.6 Hz, 1H), 4.95-4.85 (m, 2H), 4.36 (s, 2H), 4.26-4.15 (m, 2H) 4.11-3.97 (m, 2H), 3.46-3.30 (m, 3H), 1.26 (s, 2H), 1.20-1.05 (m, 2H).
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:34].[K+].O>ClC1C=CC=CC=1>[OH:34][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(O)cc3)cc2)cc1)C(=O)O

Procedure:
A solution of (2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid (85 mg) (Example 95) and KOH (100 mg) in chlorobenzene (0.3 ml) with water (1 ml) were heated in sealed tube at 200° C. for 3 days. Extracted with ethyl acetate, dried and concentrated to dryness to give a crude product which was purified by chromatography to give the title compound. MS (ES) for C26H26O7 [M+H]+: 451.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]1([CH:17]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.C(#N)C>[Cl-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18](=[O:19])[CH:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH2:22]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1cccs1)N1CCCCC1
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1cccs1)N1CCCCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
2-Chloro-1-phenylethanone (63.0 mg, 0.41 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(piperidin-1-yl)-2-(thiophen-2-yl)acetate (124 mg, 0.37 mmol) in ethyl acetate (2.5 ml) and acetonitrile (1.2 ml). The pale yellow solution was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was triturated with Et2O (8 ml). The suspension was filtered on a buckner funnel washing with Et2O (5 ml) and the solid was recovered from the filter to collect the title compound (88 mg, 48.5% yield) as a off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[C:22]([C:25]([OH:27])=O)=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.[CH3:46][N:47]([CH3:56])[CH2:48][CH2:49][CH2:50][N:51]=[C:52]=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:52][N:51]([CH2:50][CH2:49][CH2:48][N:47]([CH3:56])[CH3:46])[C:25]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:4][C:3]=3[O:2][CH3:1])=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)N(C)CCCN(C)C)n2Cc2ccccc21
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of 10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 10, Step F (0.40 g, 0.88 mmol), 3-(dimethylaminopropyl)-1-methyl amine (0.16 mL, 1.09 mmol) and 1-hydroxybenzotriazole (0.135 g, 0.96 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.19 g, 1.09 mmol) followed by N,N-diisopropylethyl amine (0.24 mL, 1.35 mmol). The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in dichloromethane afforded 0.36 g of title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2F)ccn1
Yield: 38.6 %

Procedure:
A solution of 4-chloro-2-fluoro-benzoic acid (7.0 g, 40.10 mmol), HATU (15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) and Et3N (22.4 mL, 160.4 mmol) in dichloromethane (63.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 39%), as a white solid. ESI-MS m/z calc. 280.04. found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66 (dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[F:13][C:14]([F:33])([F:32])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30]N)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C([N:36](CC)CC)C>O1CCCC1>[F:33][C:14]([F:13])([F:32])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:2]3[O:3][C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:5]([NH2:36])[N:6]=3)[CH2:25][CH2:26]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncc(-c2ccccc2)o1
Reactant: CCN(CC)CC
Reactant: NCCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Product: Nc1nc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)oc1-c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 35 mg (0.2 mmol) of 2-chloro-5-phenyloxazole in 0.5 mL of tetrahydrofuran is added, at 0° C., to a solution of 62 mg (0.2 mmol) of 4-[4-(3-trifluoromethylphenyl)piperazine-1-yl]butylamine (Example 3, step b) and 20 mg (0.2 mmol) of triethylamine in 0.2 mL of tetrahydrofuran. The mixture is stirred overnight under argon.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([C:14](OCC)=[O:15])[O:11]2)=[CH:6][CH:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][NH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([CH2:14][OH:15])[O:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCc2ccc(NC=O)cc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)OC(CO)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
A solution of ethyl 7-(formylamino)chroman-2-carboxylate (1.54 g; 6.00 mmol) in anhydrous THF, under nitrogen, is treated dropwise with a 1 M solution of lithium aluminum hydride in THF (30 mL; 30 mmol), stirred at ambient temperature for 4 h, quenched with a 10% solution of water in THF, with cooling as necessary to maintain room temperature, poured into water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a straw colored oil (1.13 g; 98% yield), identified by NMR spectral analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].IC.[C:22]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([C:16]#[N:17])=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: N#Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)c(C#N)c2ccccc21
Reaction time: 0.5 h

Procedure:
To 2-pyridin-3-yl-1H-indole-3-carbonitrile (1.0 g, 4.56 mmol) in DMF (17 mL) is added 60% sodium hydride in mineral oil (547 mg, 13.68 mmol) and the suspension is stirred for 30 min. Iodomethane (971 mg, 6.84 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added and the mixture is concentrated in vacuo. The residue is purified by purified by silica gel flash chromatography (dichloromethane-methanol gradient) to give 1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 3.83 (s, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.40-7.46 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.67-7.74 (m, 2H), 8.16 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.76 (dd, J=5.1, 1.5 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 234.1029 [(M+H)+ Calcd for C15H12N3: 234.1031].
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:19]2[CH:24]=[C:23]([O:25]CC3C=CC(OC)=CC=3)[N:22]=[C:21]([NH:35][CH:36]([CH3:38])[CH3:37])[N:20]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]([NH:35][C:21]1[NH:22][C:23](=[O:25])[CH:24]=[C:19]([C:13]2[C:12]3[C:16](=[CH:17][CH:18]=[C:10]([C:7]4[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=4)[CH:11]=3)[NH:15][CH:14]=2)[N:20]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
To a 15-mL round-bottomed flask was added N-isopropyl-5-(3-(2-(isopropylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (77 mg, 0.150 mmol) and TFA (0.3 mL, 4.04 mmol) in DCM (1 mL). The reaction was stirred at RT for 15 min and then the solvent was removed. The residue was purified with preparative HPLC (10-50% MeCN in water with 0.1% TFA in each solvent) and the fractions containing the product were combined and concentrated in vacuo to remove MeCN. The resulting mixture was extracted with CHCl3/iPrOH (4:1) and the combined organic layers were dried (MgSO4), filtered and concentrated to give 2-(isopropylamino)-6-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)pyrimidin-4(3H)-one (20.0 mg, 0.051 mmol, 33.9% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 394.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, br. s.), 10.14-10.38 (1H, m), 8.75 (1H, s), 8.15 (1H, s), 7.63-7.70 (1H, m), 7.48-7.62 (2H, m), 6.23-6.40 (1H, m), 6.03 (1H, s), 4.24 (1H, dq, J=13.3, 6.5 Hz), 3.75 (1H, dq, J=13.6, 6.6 Hz), 1.29 (6H, d, J=6.5 Hz), 1.24 (6H, d, J=6.7 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([F:27])[C:17]3[C:21]([NH2:22])=[C:20]([C:23](=[O:25])[NH2:24])[S:19][C:18]=3[CH:26]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:22][C:21]1[C:17]2[C:16]([F:27])=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]3)=[CH:26][C:18]=2[S:19][C:20]=1[C:23]([NH2:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c3c(N)c(C(N)=O)sc3c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1sc2cc(N3CCC(N)CC3)cc(F)c2c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.2 %

Procedure:
To a solution of 0.055 g (0.14 mmol) of [1-(3-amino-2-carbamoyl-4-fluoro-benzo[b]thiophen-6-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester in CH2Cl2 (1 mL) was added 0.07 mL (0.3 mmol) of a 4.0 M solution of HCl in 1,4-dioxane. The mixture was stirred at room temperature for 3 days during which time a solid precipitated from solution. The solid was collected by filtration and washed with CH2Cl2. The material was purified by reverse phase HPLC to provide 0.010 g (18%) of the title compound as a white solid. MS calc. for C14H17FN4OS [M+H]+: 309.38. Found: 309.26.
Reaction SMILES: C([S:4][CH2:5][C:6]([CH3:22])([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][C:6]([CH3:22])([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)(C)CSC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)(C)CS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to give 1-(3-mercapto-2,2-dimethyl-1-oxopropyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:50])[CH2:17][C@H:18]([NH:36][S:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)(=[O:39])=[O:38])[C:19](=[O:35])[N:20]2[CH2:25][CH2:24][O:23][CH:22]([CH2:26][O:27]CC3C=CC=CC=3)[CH2:21]2)[CH2:9]1)(=[NH:7])[NH2:6].[ClH:51]>C(O)C.[Pd]>[ClH:51].[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16](=[O:50])[CH2:17][C@H:18]([NH:36][S:37]([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=2)(=[O:39])=[O:38])[C:19](=[O:35])[N:20]2[CH2:25][CH2:24][O:23][CH:22]([CH2:26][OH:27])[CH2:21]2)[CH2:9]1)(=[NH:6])[NH2:7]
Reactant: N=C(N)N1CCCC(CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCOC(COCc3ccccc3)C2)C1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(N)N1CCCC(CNC(=O)C[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCOC(CO)C2)C1

Procedure:
A solution of the product from Example 54 in ethanol/IN hydrochloric acid is hydrogenated in the presence of 10% Pd/C for 30 hours under normal conditions. There is obtained (βS,2RS)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-2-hydroxymethyl-β-2-naphthylsulfonamido-γ-oxo-4-morpholinebutyramide hydrochloride, FAB-MS: 561 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][C:5]2([CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8]2)[O:4][CH2:3]1.C[N:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=C([N+]([O-])=O)C1=O.N>CO>[CH3:1][C:2]1([CH3:16])[CH2:7][O:6][C:5]2([CH2:14][CH2:13][CH2:12][C:11]3=[N:18][CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:10]3[CH2:9][CH2:8]2)[O:4][CH2:3]1
Reactant: CC1(C)COC2(CCCC(=O)CCC2)OC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC1(C)COC2(CCCc3ncc([N+](=O)[O-])cc3CC2)OC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
A mixture of 3,3-dimethyl-1,5-dioxaspiro[5.7]tridecan-10-one (compound of formula (Ca)) (1.32 g, 5.83 mmol), 1-methyl-3,5-dinitro-1H-pyridin-2-one (compound of formula (Cb)) (1.07 g, 5.3 mmol) and 7N ammonia solution in methanol (45 mL) was heated at 80° C. in sealed vessel overnight. The solvent was evaporated and the residue was dissolved in dichloromethane (DCM). The soluble portion was concentrated and purified by flash chromatography on silica gel (hexane/ethyl acetate, 3:1) to give the compound of formula (Cc), 5′,5′-dimethyl-3-nitro-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane] (1.5 g, 92.5%); 1H NMR (DMSO-d6, 300 MHz) 9.09 (s, 1H), 8.40 (s, 1H), 3.37 (m, 4H), 3.02 (t, 2H), 2.89 (m, 2H), 2.02 (m, 2H), 1.77 (m, 2H), 1.58 (t, 2H), 0.86 (d, 6H) ppm; MS (ES) 306.99 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27][OH:28]>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[CH:21][C:22]([O:28][CH3:27])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c3c(cccc13)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (3.2 g, 8.4 mmol, from Example M) was added to a solution of sodium hydride (0.5 g, 12.5 mmol) in methanol (100 mL). The mixture was refluxed for 8 hours and concentrated in vacuo. The solid residue was dissolved in water and acidified with concentrated HCl to pH 4. The resulting precipitate was filtered, washed with water, and dried to give 0.8 g of 2-benzyloxy-6-methoxy-benzo[de]-isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-6-methoxy-benzo[de]isoquinoline-1,3-dione (0.6 g) in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound, mp 267-269° C.;
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[ClH:1].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:31])[CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 35.2 mg (259 μmol) phenylacetic acid are dissolved in 5 ml DMF, 119 mg (1.18 mmol) triethylamine, 90.2 mg (470 μmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 127 mg (941 μmol) 1-hydroxy-1H-benzotriazole hydrate are added, while cooling with ice, and the mixture is stirred overnight at RT. The precipitate is filtered off and the filtrate is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).