Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.[CH:25]1([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26]1.[NH2:34][C:35]1[N:36]=[CH:37][N:38]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:39]=1[C:40]([NH2:42])=[O:41]>CN(C)C=O>[CH2:43]([N:38]1[C:39]([C:40]([NH2:42])=[O:41])=[C:35]([NH:34][C:31](=[O:33])[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[N:36]=[CH:37]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)CC1CCCC1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)CC2CCCC2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 54.2 %

Procedure:
4.14 ml (20 mmol) of diphenyl chlorophosphate and 2.8 ml (20 mmol) of triethylamine were added to a solution of 2.5 ml (20 mmol) of cyclopentylacetic acid in 20 ml of N,N-dimethylformamide while cooling with ice. The solution was stirred for one hour while cooling with ice. A solution of 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 in 200 ml of N,N-dimethylformamide was added to the reaction solution, followed by stirring overnight. After concentration under vacuum, 5% aqueous solution of sodium hydrogencarbonate was added to obtain a solid precipitate. The precipitate was collected by filtration using a funnel equipped with a glass filter, washed with 5% aqueous solution of sodium hydrogencarbonate and distilled water, and dried under vacuum to obtain a crude product. This crude product was purified by suspension in hot methanol to obtain 1.77 g of 1-benzyl-4-cyclopentylacetylamino-5-imidazolecarboxamide (yield 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][O:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([NH:43][NH2:44])=[O:42])=[CH:39][CH:38]=1.CCN(CC)CC>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][NH:43][C:41](=[O:42])[C:40]2[CH:45]=[CH:46][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NNC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (3.64 g, 20 mmol) in DMF (50 mL) was added HOBT (2.70 g, 20 mmol) and EDCI (3.83 g, 20 mmol). After the addition, the solution was stirred at 25° C. for 10 min then 4-methoxybenzoic acid hydrazide (3.32 g, 20 mmol) was added and followed by the addition of NEt3 (8.35 mL, 60 mmol). The solution was stirred at 25° C. overnight and water was added. The resulting suspension was filtered and the solid was washed with water. The yellow solid was dried under reduced pressure and was purified by flash chromatography (heptane/EtOAc=1:3) to give the title compound. MS: m/z 331 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:7]1[S:8][C:9]([C@@H:12]([NH2:17])[C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=1)[CH2:5][OH:6].CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29].[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CN(C1C=CC=CN=1)C>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[NH:3][C@@H:4]([C:7]1[S:8][C:9]([C@@H:12]([NH2:17])[C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=1)[CH2:5][O:6][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@H](CO)c1ccc([C@@H](N)C(F)(F)F)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc([C@@H](N)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R)-2-amino-2-{5-[(1S)-1-amino-2,2,2-trifluoroethyl]thiophen-2-yl}ethanol dihydrochloride salt (2.78 g, 8.88 mmol) in dichloromethane (49 mL) cooled to 0° C. was added Hunig's base (9.3 mL), 53.3 mmol). Allyl chloroformate (0.95 mL, 8.88 mmol) was then added and the mixture was stirred overnight at room temperature. t-butyldimethylsilylchloride (4.0 g, 26.6 mmol) and dimethylaminopyridine (0.11 g, 0.89 mmol) were then added to the solution and the solution was stirred overnight. Solvent was removed by evaporation and the resulting crude mixture was purified on silica eluting with 10% to 60% ethyl acetate in hexane to give the title compound as a colorless oil. MS: m/z=460.5 (MNa+).
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3([C:23]4[N:27]5[CH:28]=[C:29]([C:32]6[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=6)[CH:30]=[N:31][C:26]5=[N:25][CH:24]=4)[CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl.[NH2:42][C@@H:43]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([O:46]C(C)(C)C)=[O:45].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[ClH:8].[ClH:8].[CH3:54][C:51]([CH3:52])([CH3:53])[C@H:43]([NH:42][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:32]([C:29]2[CH:30]=[N:31][C:26]3[N:27]([C:23]([C:20]4([C:16]5[CH:15]=[C:14]6[C:19](=[CH:18][CH:17]=5)[N:10]=[CH:11][CH:12]=[CH:13]6)[CH2:22][CH2:21]4)=[CH:24][N:25]=3)[CH:28]=2)=[CH:33][CH:34]=1)[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (230 μL) was added to a mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid dihydrochloride (162 mg, 0.339 mmol), tert-butyl(2S)-2-amino-3,3-dimethylbutanoate hydrochloride (75.8 mg, 0.339 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (165 mg, 0.373 mmol) in methylene chloride (10 mL). The mixture was stirred at RT for 3 h, washed with NaHCO3 (7.5%) and brine, dried over Na2SO4, filtered, and concentrated. The residue [LCMS: (M+H)=576.2] was treated with HCl in 1,4-dioxane (4M, 1.0 mL) at RT for 3 h. The solvent was evaporated. The residue was washed with ether and dried to give the desired product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH:34]=[O:35])[N:33]=1>C(Cl)Cl>[CH3:28][C:29]1[N:30]([C:8]([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)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=[C:32]([CH:34]=[O:35])[N:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C=O)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (5.1 mL, 36.3 mmol) followed by trityl chloride (7.6 g, 27.2 mmol) were added to an ambient temperature solution of 2-methyl-1H-imidazole-4-carboxaldehyde (2 g, 18.2 mmol) in methylene chloride (20 mL). After stirring at ambient temperature overnight, the reaction was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 30-70% ethyl acetate/hexane afforded 2-methyl-1-trityl-1H-imidazole-4-carboxaldehyde.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16](O)=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:30]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[CH:1]1([CH2:6][CH:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([C:16]([NH2:30])=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid (100 mg, 0.24 mmol) in dry tetrahydrofuran (3 mL) under argon was treated with N-methylmorpholine (0.04 mL, 0.36 mmol) followed by iso-butylchloroformate (50 μL, 0.36 mmol). The reaction was stirred at 25° C. for 2 h, after which time, a concentrated aqueous ammonium hydroxide solution (0.2 mL) was added. The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then treated with water (5 mL), and the tetrahydrofuran was concentrated in vacuo. The product was then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 chloroform/methanol) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid amide (68 mg, 67%) as a white solid: mp 155-160° C.; EI-HRMS m/e calcd for C19H23N3O4S2 (M+) 421.1130, found 421.1135.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CCc1cnc(N2CCC(=O)CC2)nc1
Product: CCc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described for Intermediate 66.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)O>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:24]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: OC(c1ccccc1)c1ccc2ccccc2c1
Product: CC1(c2ccccc2)C(=O)C(C(c2ccccc2)c2ccc3ccccc3c2)=C1O

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with naphthalen-2-yl-phenyl-methanol to give the title compound as a colorless solid. MS: 389.5 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[N:8][N+:9]([O-:11])=[O:10])[NH:6][CH2:5][O:4][CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:6]2[CH2:5][O:4][CH2:3][N:2]([CH3:1])[C:7]2=[N:8][N+:9]([O-:11])=[O:10])=[CH:15][N:14]=1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]

Procedure:
A mixture of 1.44 g of 3-methyl-4-nitroiminoperhydro-1,3,5-oxadiazine, 2.2 g of 2-chloro-5-chloromethylpyridine, 3.7 g of potassium carbonate and 20 ml of N,N-dimethylformamide is heated for 4 hours at 50° and filtered, the filtrate is evaporated in vacuo on a rotary evaporator, and the residue is purified by chromatography [silica gel; dichloromethane/methanol (95:5)]. This gives the title compound which melts at 116 to 118°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:12](=[O:14])[CH3:13])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: Cc1cc(CO)c(CO)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(C)ncc1CO

Procedure:
2-Methyl-4,5-di(hydroxymethyl)pyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.1 mole) at room temperature overnight. The pyridine is evaporated and the residue is dissolved in 10 ml. water and extracted with 2×30 ml. of chloroform. After drying over magnesium sulfate, the chloroform is evaporated and the residue is chromatographed on a silica gel column using benzene-ethanol as eluate. By this procedure is obtained:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cc2)c2ccccc21
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of 4-(4-(piperazin-1-yl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 250 ml round-bottomed flask under an inert atmosphere. 72 ml of anhydrous dichloromethane are added and then, at 0° C., 1.22 ml of chloroethylsulphonyl chloride are added, followed by 3.67 ml of triethylamine. The reaction mixture is allowed to return gently to ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h before being diluted with dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with water, then dried over sodium sulphate, filtered through a sintered glass filter and concentrated under reduced pressure. 1.01 g of 4-[4-(4-(ethenesulphonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained in the form of a white solid, after purification on a silica column, elution being carried out with a heptane/ethyl acetate gradient varying from 95/5 to 40/60.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])=[S:31])=[CH:18][CH:17]=1
Reactant: NCCCN1CCCC1=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCCN4CCCC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 16.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (56 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (50 mg) was then added to the solution, and the mixture was stirred at room temperature for 7 hr. Next, 1-(3-aminopropyl)pyrrolidone (50 mg) was added thereto, and the mixture was further stirred at room temperature for 13 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (15 mg, yield 17%).
Reaction SMILES: B(F)(F)F.C(O)(=O)C.[CH2:9]([SH:12])[CH2:10][SH:11].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31](=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.CCOCC>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:12][CH2:9][CH2:10][S:11]2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Reactant: SCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(CCC2(c3ccccc3)SCCS2)CC1
Reaction time: 6 h
Yield: 92.7 %

Procedure:
Boron trifluoride-acetic acid complex (BF3.2-CH3CO2H, 0.370 mL, 501 mg, 2.67 mmol) was added to a solution of 1,2-ethanedithiol (0.440 mL, 494 mg, 5.25 mmol) and (1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine (930 mg, 2.65 mmol) in methylene chloride (4.0 mL) at rt. After 6 h, the mixture was diluted with ether (50 mL) and washed with saturated aq. sodium bicarbonate (2×25 mL), 2.5 N aq. NaOH (25 mL), and saturated aq. brine (25 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ethyl acetate in hexane, to give 1.05 g of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10]C(=O)C.CC(O)=O.[N:18](OCCC(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([CH3:9])[CH:5]=1)[NH:10][N:18]=[CH:1]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1c(C)cc(C)cc1C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2[nH]ncc2c1
Yield: 100.3 %

Procedure:
N-(2,4,6-trimethyl-phenyl)-acetamide (23.8 g, 133 mmol) (prepared as described in Example 12) was dissolved in a mixture of toluene (300 mL) and glacial AcOH (10.4 g, 173 mmol, 1.3 eq) and then treated slowly with isoamyl nitrite (20.3 g, 23.2 mL, 173 mmol, 1.3 eq). The mixture was heated at reflux overnight or until all the starting material was consumed as judged by TLC (30% EtOAc-hexanes). The solution was then poured into H2O (1.3 L) and extracted with EtOAc (2×300 mL). The combined organic extracts were then washed with saturated aq. NaHCO3 solution (2×200 mL) and brine (1×100 mL). The extracts were dried (MgSO4), filtered, and concentrated to provide 19.5 g of 5,7-dimethyl-1H-indazole 2 as a red waxy solid. This material was carried on without additional purification. RP-HPLC Method: 2-100% B in 2 minutes
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(CN)CC1>CN(C=O)C>[CH:54]1([CH2:53][NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:56][CH2:55]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 1-cyclopropylmethanamine (7.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.2 mg, 18%). LC-MS m/z 627 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[OH:6][CH2:7][CH:8]([NH:11][CH2:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=2[NH:15][CH:14]=1)[CH2:9][OH:10].[O:23]1CC(O)O[CH2:25][CH:24]1O>CO>[ClH:5].[OH:22][C:21]1[C:16]2[NH:15][CH:14]=[C:13]([CH2:12][N:11]([CH2:25][CH2:24][OH:23])[CH:8]([CH2:7][OH:6])[CH2:9][OH:10])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: OC1COC(O)CO1
Reactant: O=c1[nH]cnc2c(CNC(CO)CO)c[nH]c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCCN(Cc1c[nH]c2c(O)ncnc12)C(CO)CO
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Sodium cyanoborohydride (0.011 g, 0.18 mmol) was added to a solution of the product from Example 10.2 (0.041 g, 0.15 mmol) and 1,4-dioxane-2,5-diol (0.027 g, 0.22 mmol, Sigma-Aldrich) in MeOH (3 ml) and stirred at it for 16 h. The solvent was evaporated and the residue chromatographed on silica gel (iPrOH-28% aq. NH4OH-water, 98:1:1) to give the crude product as a yellow solid (˜21 mg). The solid was triturated with a little 7M NH3-EtOH solution to leave the free base form of the title compound as a colourless solid (˜12 mg). This solid was dissolved in excess 5% aq. HCl then the solvent evaporated to give 7-(((1,3-dihydroxypropan-2-yl)(2-hydroxyethyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one hydrochloride as a solid (15 mg, 32%). 1H NMR (D2O, referenced to HOD at 4.72 ppm) δ 8.49 (s, 1H), 7.82 (s, 1H), 4.77 (s, 2H), 3.98-3.88 (m, 6H), 3.77 (sextet, J=6.1 Hz, 1H), 3.56 (br. s, 2H). 13C NMR (D2O), δ 154.4, 144.4, 139.5, 132.8, 118.6, 104.1, 64.3, 56.7, 55.7, 52.6, 47.1. +ESMS Found 283.1407 (M+H)+ C12H19N4O4 requires 283.1406.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:37])[NH:21][C@@H:22]([C:34](=[S:36])[NH2:35])[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34](=[S:36])[NH2:35])[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:37]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
N-Methyl-N-((1R)-2-(2-naphthyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester (0.25 g; 0.462 mmol) was dissolved in methylene chloride (1.5 ml) and trifluoroacetic acid (1.5 ml) was added. The reaction mixture was stirred 1 h at RT. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (5 ml) and washed with aqueous sodium hydrogencarbonate (5 ml). The organic phase was dried (Magnesium sulfate) and the solvent was removed in vacuo to afford 0.201 g of (2R)-2-methylamino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-thiocarbamoylethyl)propionamide.