Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: CN1CCN(CCCOc2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCN(C)CC4)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.311 mmol), 1-(3-(4-bromophenoxy)propyl)-4-methylpiperazine (130 mg, 0.373 mmol), 2.0M aqueous potassium carbonate (0.50 mL, 1.0 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (80 mg, 75% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[S:10])[NH2:9])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Ca+2].Br[CH:17]1[C:22](=O)[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]1>CC(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[S:10][C:17]3[CH2:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][C:22]=3[N:9]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CCOC(=O)N1CCc2nc(Cc3ccncc3)sc2C1
Temperature: 25 °C
Yield: 70 %

Procedure:
2-(Pyridin-4-yl)ethanethioamide (6 mmol) and 20 mmol of calcium carbonate were added to a solution of ethyl 3-bromo-4-oxopiperidine-1-carboxylate (1 g; 4 mmol; cf. AMN-01) in 20 ml of 2-propanol. The reaction mixture obtained was heated under reflux for 20 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 25° C. and filtered over Celite. The filter cake was washed several times with ethyl acetate. The organic phase was concentrated under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed successively with water and saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate, the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (30% ethyl acetate in hexane). The desired product was obtained in a yield of 70%.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.C(Cl)CCl.[CH3:10][S:11][C:12](SC)=[CH:13][N+:14]([O-:16])=[O:15]>C(Cl)CCl>[CH3:1][NH:2][CH:12]([S:11][CH3:10])[CH2:13][N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Solvent: ClCCCl
Product: CNC(C[N+](=O)[O-])SC

Procedure:
A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 33% ethanolic methylamine in 0.8 liters of ethylene dichloride; 0.9 4 mole) was added over 51/2 hr at 70° to a stirred solution of 1,1-bismethylthio-2-nitroethene (99.0 g, 0.6 mole) in ethylene dichloride (1.5 liters). The solution was heated to boiling and 0.7 liters of solvent were distilled off. The cooled solution was washed with 2 N hydrochloric acid (0.25 liters), then with brine (0.25 liters). The solvent was removed and the residue crystallised from isopropyl acetate (0.5 liters), treating the hot solution with charcoal (10.0 g). The product (35.0 g) formed yellow prisms, m.p. 114°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:13]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:14]([C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)([CH3:19])[CH3:18])=[CH:15][N:16]=2)=[CH:6][C:3]=1[C:4]#[N:5].[N-:36]=[N+:37]=[N-:38].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][C:12]2[N:13]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:14]([C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)([CH3:18])[CH3:19])=[CH:15][N:16]=2)=[CH:6][C:3]=1[C:4]1[NH:38][N:37]=[N:36][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(C#N)c3)n2-c2ccc(F)cc2)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(-c4nnn[nH]4)c3)n2-c2ccc(F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of 2-chloro-5-((5-(2-(3-chloro-4-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)benzonitrile (104 mg, 0.20 mmol), sodium azide (130 mg, 2.0 mmol, 10.0 eq) and NH4Cl (110 mg, 2.0 mmol) in DMF (2 mL, anhyd) was stirred at 110° C. for 16 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The combined extracts were washed with water and brine, then dried over MgSO4 and concentrated. Purification by column chromatography (silica, 0 to 20% MeOH/DCM) provided the title compound (85 mg, 76%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.18-7.14 (m, 2H), 6.95-6.89 (m, 3H), 6.78-6.74 (m, 2H), 6.37-6.31 (m, 2H), 4.17 (s, 2H), 3.81 (s, 3H), 1.39 (s, 6H); MS (EI) m/z 569 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH2:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:26][S:31]([CH3:30])(=[O:33])=[O:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 69 mg (0.16 mmol) of (3S,5R,6S)-3-allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 28, Step B from the non-racemic precursor described in Example 19, Step A) in 1.6 mL of DCM was added methanesulfonyl chloride (13.7 μL, 0.175 mmol) and pyridine (38.7 μL, 0.478 mmol) successively at 0° C. After being stirred at rt for 14 h the reaction mixture was acidified with 10% aq. citric acid and extracted (2×DCM). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase HPLC (40 to 90% MeCN/H2O in 45 min, 2 injections, tR=25.94 min) provided the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc2cc(Br)ccc21
Reactant: COc1cccc(B(O)O)c1
Product: CCCCn1ccc2cc(-c3cccc(OC)c3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 3-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 280. 1HNMR (300 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.52 (d, 1H, J=8.30 Hz), 7.43-7.38 (m, 2H), 7.39(dd, 1H, J=7.70 and 7.91 Hz), 7.22 (d, 1H, J=8.50 Hz), 7.17 (s, 1H), 6.85 (d, 1H, J=7.10 Hz), 6.46 (d, 1H, J=3.05 Hz), 4.18 (t, 2H, J=7.01 Hz), 3.81 (s, 3H), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.87 ppm (t, 3H, J=7.31 Hz). Elemental Analysis for C19H21NO: Calculated: C, 76.18; H, 6.39; N, 4.94. Found: C, 76.85; H, 6.23; N, 4.81.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])=[O:4].C([SiH](CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[F:26][C:2]([F:1])([F:27])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([NH2:25])=[N:11][C:12](=[O:24])[N:13]([CH:23]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])=[O:4]
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C#CCNC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC[SiH](CC)CC
Agent: [OH-]
Solvent: CO
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1CCCNC(=O)C(F)(F)F
Reaction time: 22 h
Yield: 67.2 %

Procedure:
5-[3-(trifluoroacetamido)propynyl]cytidine (1.25 g, 3.19 mmol, 1.00 equiv.) was dissolved in methanol (30 mL). Palladium hydroxide (0.25 g, 20 wt./wt. % based on propynyl cytidine) and triethylsilane (3.71 g, 31.90 mmol, 10.00 equiv.) were added to the reaction mixture. After 20-24 hours at ambient temperature, the reaction mixture was filtered through glass fiber and the filtrate was concentrated under reduced pressure giving a dark brown residue. The residue was purified by flash chromatography. Removal of solvent from the appropriate fractions afforded 0.85 g (71%) of 5-[3-(trifluoroacetamido)propyl]cytidine as a cream colored solid, which was confirmed by 1H-NMR.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][S:12]([NH2:15])(=[O:14])=[O:13].[Cl:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:23](Cl)[N:22]=[C:21]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[N:20]=1>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[N:22]=[C:23]([NH:15][S:12]([CH2:11][CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[CH3:7])(=[O:14])=[O:13])[C:24]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CC(C)(C)CCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCCC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
Caesium carbonate (2.62 g) was added to a solution of 4,4-dimethylpentane-1-sulphonic acid amide (720 mg) and 4,6-dichloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidine (Can. Pat. Appl. 2071193) (1.40 g) in dry N,N-dimethyl formamide (8 ml) and the resulting mixture stirred at 80° C. for 4 hours under nitrogen. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (40 ml) and 2N aqueous hydrochloric acid (20 ml). The organic phase was separated, washed (brine 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 100:0 changing to 99:1 gave crude product which was recrystallised from ethyl acetate:pentane to give N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-4,4-dimethyl-1-pentanesulfonamide as a white solid (1.08 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[CH3:14][N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25][NH2:26])[CH2:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N:18]4[CH2:19][CH2:20][CH2:21][N:15]([CH3:14])[CH2:16][CH2:17]4)[CH:23]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: CN1CCCN(c2cccc(CN)c2)CC1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN1CCCN(c2cccc(CNc3ccc4c(=O)[nH]nc(Cl)c4c3)c2)CC1
Yield: 18.9 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), 3-(4-methyl-[1,4]diazepan-1-yl)-benzylamine (112 mg, 0.654 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-[3-(4-methyl-[1,4]diazepan-1-yl)-benzylamino]-2H-phthalazin-1-one hydroformate (29 mg) as a pale brown solid. 1H (400 MHz, d6-DMSO) δ: 1.83 (m, 2H), 2.21 (s, 3H). 2.39 (m, 2H), 2.54 (m, 2H), 3.38 (m, 2H), 3.46 (m, 2H), 4.32 (d, 2H), 6.56 (m, 2H), 6.71 (s, 1H), 6.83 (s, 1H), 7.09 (t, 1H), 7.16 (dd, 1H), 7.61 (m, 1H), 7.90 (d, 1H), 8.19 (s, 1H), 12.33 (s, 1H) ppm; m/z (M+1) 398.04.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO[C:27](OC)([CH3:29])[CH3:28].CS(O)(=O)=O>CC(C)=O>[C:1]([CH2:3][C@H:4]1[O:24][C:27]([CH3:29])([CH3:28])[O:23][C@@H:6]([CH2:7][C:8]([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5]1)#[N:2]
Reactant: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide, approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane (160 mL, 1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) is added, and the solution is stirred for 2 hours at room temperature. The reaction is quenched by the addition of aqueous sodium bicarbonate (800 mL) and ethyl acetate (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give 62.5 g of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl -1,3-dioxane-4-acetamide as an off-white crystalline solid (mp 98°-100° C., uncorrected).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C)C=O>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][C@H:7]2[CH2:6][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.0 g) in dimethylformamide (90 ml) was added piperazine (2.0 g) and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)pyrrolidine (2.52 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>O1CCOCC1>[CH2:31]([NH:35][C:27]([NH:28][C:22]1[CH:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1)=[O:26])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCN
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CCCCNC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of dioxane and 41.3 mg of butan-1-amine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 150.7 mg of 1-butyl-3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)urea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=614.1)=93%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[N:23]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 56.1 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (106 mg, 0.393 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.179 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (89 mg, 56%). 1H NMR (500 MHz, CD3OD) δ ppm 1.36 (ddd, J=13.42, 6.59, 1.46 Hz, 3 H), 2.01 (d, J=1.46 Hz, 2 H), 2.15 (d, J=1.95 Hz, 1 H), 2.18-2.21 (m, 1 H), 2.32 (d, J=1.46 Hz, 2 H), 3.86 (d, J=1.46 Hz, 3 H), 5.38-5.49 (m, 1 H), 6.67 (dd, J=2.20, 1.22 Hz, 1H), 7.58 (dd, J=2.93, 1.46 Hz, 1 H), 7.69 (d, J=5.86 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H21N9O, 404; found 404.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([NH2:43])[CH:37]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>CO>[ClH:44].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCCOc2ccc(N)c(N)c2)C1
Agent: Cl
Solvent: CO
Product: Nc1ccc(OCCOC2CNCCC2c2ccc(OCCCOCc3ccccc3)cc2)cc1N

Procedure:
In an analogous manner to that described in Example 22(l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[2-(3,4-diamino-phenoxy)-ethoxy]-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 4-[2-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxy]-ethoxy]-benzene-1,2-diamine hydrochloride (1:3) as pale violet crystals; MS: 492 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[C:18]([CH3:41])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C@H:6]1[C:5]2[CH:14]=[CH:15][C:2]([O:1][CH2:39][C:35]3[CH:34]=[C:33]([C:19]4[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:17]([Cl:16])[C:18]=4[CH3:41])[CH:38]=[CH:37][CH:36]=3)=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.237 g, 1.14 mmol), (3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.475 g, 1.14 mmol) and tributylphosphine (0.453 mL, 1.82 mmol) in toluene (18 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.459 g, 1.82 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (9 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.622 g, yield 89%) as a yellow oil.