Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]([C:29]2[S:30][C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]([CH3:34])[N:33]=2)[C:25](=[O:40])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][N:26]([C:29]4[S:30][C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:32]([CH3:34])[N:33]=4)[C:25](=[O:40])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)c1sc(-n2ccc(Cl)cc2=O)nc1C
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-n2ccc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OCC)C3)cc2=O)nc1C
Yield: 6.5 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), ethyl 2-(4-chloro-2-oxopyridin-1(2H)-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (140a) (106 mg, 0.355 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMSO (1 mL). The suspension was subjected to same operation as in Example (131b) to obtain 10.8 mg of the title compound as a pale yellow solid (6%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][PH:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])=[O:7])[CH3:4].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>O1CCCC1>[CH2:3]([O:5][P:6]([C:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH3:9])([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:7])[CH3:4]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)(OCC)P(=O)(CC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
21 g of 99% sodium hydride are suspended at room temperature under argon in 1000 ml of anhydrous tetrahydrofuran, and a solution of 172.2 g of 1,1-diethoxyethylphosphinic acid ethyl ester is added dropwise over a period of 2.5 hours, the temperature being maintained at from 20° to 25°. The reaction is exothermic and involves the evolution of gas. The batch is then stirred for 1.5 hours at room temperature, 142.2 g of bromomethylcyclohexane are added and heating under reflux is effected for 24 hours. The suspension is cooled to 4° and 250 ml of water are carefully added. Two phases are formed. The tetrahydrofuran phase is separated off and the aqueous phase is extracted twice with 250 ml of dichloromethane each time. Concentration by evaporation yields a brown oil which, after distillation under reduced pressure, gives 1,1-diethoxyethyl(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 95° (1.8×10-4 mbar).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:12]([C:17](OC1C=CC([N+]([O-])=O)=CC=1)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15].CCN(CC)CC.[CH3:43][C:44]1[CH:73]=[CH:72][CH:71]=[CH:70][C:45]=1[CH2:46][NH:47][C:48]([C@@H:50]1[C:54]([CH3:56])([CH3:55])[S:53][CH2:52][N:51]1[C:57](=[O:69])[C@@H:58]([OH:68])[C@@H:59]([NH2:67])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:49]>CN(C=O)C.C(OCC)(=O)C>[CH3:43][C:44]1[CH:73]=[CH:72][CH:71]=[CH:70][C:45]=1[CH2:46][NH:47][C:48]([C@@H:50]1[C:54]([CH3:56])([CH3:55])[S:53][CH2:52][N:51]1[C:57](=[O:69])[C@@H:58]([OH:68])[C@@H:59]([NH:67][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:49]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@@H](N)Cc2ccccc2)CSC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CSC1(C)C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
HOBt (0.41 g), Boc-Asn-ONp (1.27 g), and Et3N (0.92 ml) were added to a solution of H-Apns-Dmt-NHBzl(2-Me) (1.32 g) obtained in the step 2 of Example 3 in DMF (20 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% NaHCO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from AcOEt/n-hexane to obtain the title compound (1.79 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([NH:17][CH:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].[C:33](O)(=O)C>CN(C=O)C.CI.C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([N:17]([CH:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH3:33])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: c1cncc(C(Nc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(c1cccnc1N1CCOc2ccccc21)C(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-(dipyridin-3-ylmethyl)pyridine-3-amine (82 mg, 0.207 mmol) in dry DMF (1.5 mL) was added 60% sodium hydride/mineral oil (16 mg, 0.40 mmol) and let stir at ambient temperature for 15 minutes. Over a one hour period methyl iodide (3 drops) was added. The reaction was diluted with ethyl acetate, neutralized with acetic acid, and washed with water (3×). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-90% acetone/hexane gradient to give the title compound as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.50 (2H, d, J=4.6 Hz), 8.19 (2H, s), 8.16 (1H, d, J=4.4 Hz), 7.25 (2H, d, J=6.4 Hz), 7.15-7.17 (2H, m), 7.01 (21H, m), 6.75-6.84 (4H, m), 6.57 (1H, d, J=7.8 Hz), 6.01 (1H, s), 4.16 (2H, t, J=4.4 Hz), 3.86 (2H, t, J=4.4 Hz), 2.53 (3H, s). m/e (m+1): 410.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:14]=1[C:15]([NH:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CCCSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-t-butoxycarbonylaminopropoxy)-4-(propylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a solid product (2.82 g, 90%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14](O)[CH3:15])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[NH:26]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:27]([C:36](O)=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.C1C=NC2N([OH:55])N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C@@H:27]([NH:26][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:36]([N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:14][CH2:15][OH:55])[CH2:4][CH2:3]2)=[O:37])=[CH:34][CH:33]=1
Reactant: On1nnc2cccnc21
Reactant: CC(O)c1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Yield: 74.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) using 1-(2-(4-piperidyl)phenyl)ethan-1-ol hydrochloride (Step c) (0.72 g, 3.0 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (5 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (1.09 g). MS (EST, pos. ion) m/z. 487 (M+1); MS (ESI, neg. ion) m/z: 485 (M−1). Calc'd for C27H35ClN2O4: 486.23.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH2:15]Br)[CH2:5]1)=[N+:2]=[N-:3].[N-:27]=[N+:28]=[N-:29].[Na+].O.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[N:1]([C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH2:15][N:27]=[N+:28]=[N-:29])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CN=[N+]=[N-])CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3α-azido-21-bromo-5α-pregnan-20-one (35 mg, 0.083 mmol) in DMSO (3 mL) was treated with sodium azide (33 mg, 0.5 mmol) and the resulting mixture was stirred at RT for 24 h. Addition of water and ethyl acetate and extraction of the organic layer with water, brine, drying (Na2SO4) and evaporation of the solvent in vacuo afforded after purification of the residue using flash colunm chromatography with dichloromethane/ethyl acetate 90/10 as elution solvent the compound named above.
Reaction SMILES: [CH3:1][Mg]I.Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: C[Mg]I
Reactant: Brc1cccc2cnccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2cnccc12

Procedure:
A 3M solution of methyl magnesium iodide in ether (50 ml, 0.15 mol) was added dropwise to a stirred, ice-cooled solution of 5-bromoisoquinoline (21 g, 0.10 mol), obtained by the method described in J. Org. Chem., 1964, 29, 329, and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (400 mg, 0.7 mmol) in anhydrous ether and the reaction mixture heated under reflux for 5 days, allowed to cool, then poured into water (500 ml). The organic phase was separated, combined with ether extracts of the aqueous phase, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield an oil, chromatography of which on silica gel, using a 5-50% ether in hexane elution gradient, provided the required product (8.4 g). Rf 0.40 (SS 8), m/e 144 (M+H)+. Found: C,79.57; H,6.26; N,8.61. C10H9N; 0.27 C4H8O2 requires C,79.70; H,6.74; N,8.39%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=2[O:16][CH3:17])[N:6]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:28]([C:20]2[CH:19]=[N:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:29])[S:3][CH:4]=1
Reactant: COc1cc(C)cc(OC)c1-c1csc(N)n1
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cnc3ccccc3c2)n1
Reaction time: 48 h
Yield: 97.5 %

Procedure:
1 g of 2-amino-4-(2,6-dimethoxy-4-methylphenyl)-thiazole, 0.76 g of 3-quinolinecarboxylic acid, 0.65 ml of triethylamine and 2.15 g of BOP are dissolved in 10 ml of DMF, and the reaction mixture is left at r.t. for 48 hours. It is then poured into pH 2 buffer solution, a precipitate is separated by filtration, and the yellow solid is successively washed with water, stirred in 5% sodium carbonate solution, filtered off and thereafter dissolved in DCM. The solution is washed with 5% sodium carbonate solution and then, successively, the organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is stirred in ether, filtered off and dried to yield 1.58 g of the expected compound, m.p.=245°246° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=O)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].[CH3:41][OH:42]>ClC(Cl)C.CC(O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH2:24][N:30]2[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]2)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:28])([F:29])[F:27])[CH:6]=1)([CH3:3])[CH3:2].[C:41]([OH:35])([C:26]([F:29])([F:28])[F:27])=[O:42]
Reactant: CO
Reactant: O=C(O)C1CNC1
Reactant: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)c(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(CN4CC(C(=O)O)C4)ccc2-3)c(C(F)(F)F)c1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 17C, 0.22 g, 0.548 mmol) in dichloroethane (2 mL) and methanol (2.000 mL) were sequentially added azetidine-3-carboxylic acid (0.066 g, 0.658 mmol) and 8 drops of AcOH at room temperature. The contents were heated at 80° C. for 75 minutes. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (0.041 g, 0.658 mmol) was added in one lot. The contents were stirred at room temperature for 30 minutes. The reaction mixture was concentrated, dissolved in acetonitrile (1.5 mL), and subjected to prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were concentrated and freeze dried to yield 1-((3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.135 g, 0.225 mmol, 41.0% yield) as a tan solid. The compound had an HPLC retention time=3.01 min (condition C); LC/MS M+1=487.2; 1H NMR (500 MHz, MeOD) δ ppm 8.01 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=8.6 Hz), 7.50 (1H, s), 7.48 (1H, dd, J=8.0, 1.7 Hz), 7.36 (1H, d, J=2.5 Hz), 7.31 (1H, dd, J=8.6, 2.5 Hz), 4.79 (1H, spt, J=6.1 Hz), 4.46 (2H, s), 4.32-4.41 (4H, m), 3.71 (1H, quin, J=8.3 Hz), 3.04 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.2 Hz), 1.39 (6H, d, J=6.1 Hz).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.[NH3:19]>>[NH2:19][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: N
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
CH-A-640 873 describes the reaction of 1,4-dihydroxyanthraquinone with ammonia in aqueous phase to form 1-amino-4-hydroxyanthraquinone.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: O=Cc1c[nH]cn1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=Cc1cn(-c2nc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cn1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.056 mmol) was mixed with 1H-imidazole-4-carbaldehyde (16 mg, 0.168 mmol) in isopropanol (2 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-imidazole-4-carbaldehyde as a crude mixture which was taken on to the next step without further purification. LCMS (ES):>95% pure, m/z 380 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH2:16])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:17]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[C:18]=[S:19]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:18](=[S:19])[NH:17][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(N)c2cccs2)c1
Reactant: CC(=O)OCCN=C=S
Solvent: Cc1ccccc1
Product: CC(=O)OCCNC(=S)NC(Cc1cc(C)cc(C)c1)c1cccs1
Yield: 25.7 %

Procedure:
A solution of 2-(3,5-dimethyl-phenyl)-1-thiophen-2-yl-ethylamine (1.4 g, from example 1) and acetic acid 2-isothiocyanato-ethyl ester (0.75 g, prepared according to Collect. Czech. Chem. Commun. 1986, 51, 112-117) in toluene (15 ml) was stirred at room temperature for 12 h, evaporated and the residue purified by column chromatography to yield the product (0.5 g) as a yellowish oil.
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C:3]([OH:5])=O.Cl.[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[NH:6][CH:2]([C:3](=[O:5])[NH:18][CH2:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1)C(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available N-α-CBZ-L-alanine (2.11 g, 9.5 mmol) in dichloromethane (50 mL) was added 2-aminoacetophenone hydrochloride (1.62 g, 9.5 mmol). The resulting solution was cooled to 0° C. and N-methylmorpholine (1.15 g, 11 mmol), 1-hydroxybenzotriazole (2.55 g, 18.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.35 g, 12.3 mmol), in that order, were added under an Argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous NaHCO3 solution; the separated organic phase was washed with 2N citric acid, saturated NaHCO3 solution and brine, then dried over MgSO4 overnight. After filtration and concentration, the residue was purified by column chromatography on silica gel (eluent, EtOAc:hexane-1:1) to yield the title compound, [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester.
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=[O:8])[CH2:4][OH:5].C(N(CC)CC)C.[CH:45]([Si:48](Cl)([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])([CH3:47])[CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=[O:8])[CH2:4][O:5][Si:48]([CH:52]([CH3:54])[CH3:53])([CH:49]([CH3:51])[CH3:50])[CH:45]([CH3:47])[CH3:46]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Reaction time: 20 h
Yield: 90.5 %

Procedure:
N-[(1R,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (883 mg, 1.65 mmol) synthesized in Example (91a), triethylamine (1.15 mL, 8.27 mmol) and 4-dimethylaminopyridine (404 mg, 3.31 mmol) were dissolved in methylene chloride (20 mL), and triisopropylsilyl chloride (0.60 mL, 2.81 mmol) was added at room temperature, followed by stirring for 20 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired compound (1.03 g, 90%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[N:11](CC3C=CC(OC)=CC=3)[C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)=[CH:4][N:3]=1.C(#N)C>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[NH:11][C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cnc(N)nc3)c3cc(Cl)ccc32)cc1
Solvent: O
Solvent: CC#N
Product: Nc1ncc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Ceric ammonium nitrate (201 mg, 2.6 eq) was added portionwise to a stirred solution of 5-(2-aminopyrimidin-5-yl)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (75 mg) in 9:1 acetonitrile:water (9 mL:1 mL). The reaction was stirred at room temperature overnight, and then another 200 mg of ceric ammonium nitrate was added. The reaction was stirred another 3 h, and then concentrated in vacuo. The crude was partitioned between EtOH and saturated potassium carbonate. The aqueous layer was re-extracted with ethanol 4×. The combined extracts were then dried over sodium sulfate, then concentrated and purified by chromatography (Gradient: 3:1 hexanes:EtOAc to EtOAc) yielding product (44 mg, 76% yield). 1HNMR (300 MHz, DMSO-d6) δ10.78 (s, 1H), 8.18 (s, 2H), 7.62 (d, 1H), 7.50-7.13 (m, 8H), 3.70 (m, 1H), 3.50-3.32 (m, 2H). HRMS (ES+) m/z calcd for C20H15Cl2N5O [M+H]+, 412.0732. found, 412.0726.