Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:12].Cl>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (405 mg) and 2-bromo-4'-hydroxyacetophenone (646 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature, giving a clear solution. A precipitate had formed after an hour. After 231/2 hours, 2N-hydrochloric acid (5 ml) was added to the suspension and the solid was collected. This was washed with ethanol to give the title pyrimidinone (679 mg,); m.p. 260° with decomposition; λmaxEtOH 224 nm (ε 17300), 282.5 nm (ε 15660), 353 nm (ε 4900).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[N:26]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[S:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]3)=[CH:4][N:5]=1)=[CH:16]2)(=[O:19])=[O:20]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: O=S(=O)(Nc1cccc2cc(-c3ncc(CCl)s3)[nH]c12)c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.460 g) in N,N-dimethylformamide (12 ml) were added ethyl piperazin-1-ylacetate (0.385 g) and triethylamine (0.31 ml), and the mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-hexane to give the title compound (0.507 g, yield 83%) as colorless crystals.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([NH:26][C:27]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: c1ccccc1
Solvent: O
Product: S=C(Nc1ccccc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate (1.31 g, 0.005 mole) was dissolved in benzene (125 ml) and phenyl isothiocyanate (0.74g, 0.0055 mole) added dropwise with stirring. After 24 hr., the mixture was filtered to give the title compound (free base) as a white amorphous solid (1.76g). This was dissolved in a minimum of hot ethanol, saturated ethanol-HCl added until acid, and then the solution allowed to crystallise. Filtration afforded the title compound hydrochloride as colourless prisms (1.75g), m.p. 224.8°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH2:41])=[O:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH:41][CH2:31][C:29]1[O:30][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[CH:3]=2)[N:7]=[CH:8]3)=[CH:27][CH:28]=1)=[O:38]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Reactant: CP(C)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CP(C)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Temperature: 25 °C
Yield: 43 %

Procedure:
5-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-carbaldehyde and 2-(dimethylphosphinoyl)ethanamine (compound 2.2, 82 mg) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (237 mg) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid (138 mg). LCMS ESI(+) m/z: 569 (M+1). Yield: 43%. 1H NMR (300 MHz, CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.18 (m, 1H), 8.12 (m, 2H), 7.76 (m, 1H), 7.68 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.03 (m, 2H), 6.92 (m, 3H), 6.46 (d, 1H), 5.69 (s, 2H), 3.91 (s, 2H), 2.99 (m, 2H), 2.10 (m, 2H), 1.52 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:35]=[C:34]([O:33][CH3:32])[C:39]=1[O:40][CH3:41]
Reactant: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(CNC(C)=O)cc4)c3c2)cc(OC)c1OC
Yield: 53.1 %

Procedure:
N-{4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzyl}-acetamide (Intermediate CC, 24 mg, 0.048 mmol), 3,4,5-trimethoxyphenyl boronic acid (13 mg, 0.058 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.002 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (2 ml) and heated in a microwave reactor at 150° C. for 20 min. EtOAc was added, washed with water, dried and purified by silica gel chromatography eluting with 0-4% MeOH:DCM to give 11 mg (53%) of the title compound. MS ESI (m/z): 432.2 (M+1)+, calc. 431.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=[C:11]([Br:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-].CP(C)C.[ClH:20]>O1CCCC1.C(#N)C>[ClH:20].[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=1)[O:7][CH2:6][CH2:5][C@H:4]2[NH2:1]
Reactant: [N-]=[N+]=N[C@@H]1CCOc2c(Br)cc(Br)cc21
Agent: CP(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: N[C@@H]1CCOc2c(Br)cc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cooled solution of 4(R)-azido-6,8-dibromo-chroman in tetrahydrofuran (0.16M) was added 1.2 equivalents of trimethylphosphine. The mixture was warmed to room temperature and maintained for 16 h. Concentration of the mixture gave the crude amine. This was dissolved in acetonitrile (0.20M) and 2 equivalents of hydrochloric acid added. The mixture was stirred for 16 h and the solids filtered, washed with acetonitrile and dried to afford the title compound as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:6][Si:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][CH2:2][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCCOc1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
3-Chloropropyltrimethylsilane (33.14 g, 0.22 mol) is added dropwise, over 10 minutes, to a mixture of 4-hydroxybenzaldehyde (24.4 g, 0.2 mol) and of potassium carbonate (30.4 g, 0.22 mol) in 150 ml of dry DMF heated to 120° C. under nitrogen. The reaction mixture is left for 2 hours 30 minutes at 120–130° C. It is cooled and poured into ice-cold water. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are dried over sodium sulfate and concentrated under vacuum. After vacuum distillation (0.2 mmHg), 40.5 g (yield: 86%) of 4-(3-trimethylsilanylpropyloxy)benzaldehyde are obtained in the form of a colorless oil which distils at 110–114° C. and which is used as it is in the next step.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][CH:9]1[OH:10])=[O:6])=[N+:2]=[N-:3].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:10][CH:9]1[O:11][C@H:12]([CH2:17][O:18][C:23](=[O:25])[CH3:24])[C@@H:13]([O:16][C:12](=[O:11])[CH3:13])[C@H:14]([O:15][C:9](=[O:10])[CH3:8])[C@@H:8]1[NH:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:6])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
A solution of 20 (25 mg, 0.095 mmol) in pyridine (2 mL) was cooled to 0° C. To this solution was added acetic anhydride (1.0 ml, 11 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (1×50 mL), water (1×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:10 to 1:2 EtOAc/hexanes to afford 39 mg (95%) of a light yellow oil. IR (thin film): 3317, 2106, 1744, 1677, 1529 cm−1. 1H NMR (500 MHz, CDCl3): δ2.05 (app s, 6H), 2.10 (s, 3H), 2.12 (s, 3H), 3.82 (ddd, 1H, J=2.4, 4.5, 9.6), 3.93 (s, 2H), 4.13 (dd, 1H, J=2.4, 12.6), 4.29 (dd, 1H, J=4.5, 12.6), 5.15 (app t, 1H, J=9.6), 5.21 (app t, 1H, J=5.7), 5.78 (app t, 1H, J=4.5), 6.37 (d, 1H, J=5.7). 13C NMR (125 MHz, CDCl3): δ20.5, 20.5, 20.6, 20.6, 20.6, 20.8, 20.8, 51.2, 52.4, 52.5, 53.2, 61.4, 61.5, 67.4, 67.6, 69.8, 70.3, 72.0, 72.1, 72.9, 90.2, 92.1, 166.9, 168.6, 169.1, 169.2, 170.6, 170.8, 171.5. HRMS (FAB) m/z 437.1496 (MLi+C16H22LiN4O10 requires 437.1496).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C.S(=O)(=O)(O)O.O[CH2:22][NH:23][C:24](=[O:27])[CH2:25][Cl:26]>O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[C:8]([CH2:22][NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(CCl)NCO
Reactant: CC1CCc2cc(O)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2cc(O)c(CNC(=O)CCl)cc21
Reaction time: 2 h

Procedure:
A solution of 850 mg of 1 methyl-5-indanol in 5 ml of a mixed solution of acetic acid and sulfuric acid (10:1 by volume) solution was mixed with 850 mg of N-hydroxymethyl chloroacetamide at room temperature under stirring for 2 hours. After reaction the reaction mixture was poured into 20 ml of water, extracted with ethyl acetate. The extract was washed with water, dried with anhydrous magnesium sulfate and concentrated under vacuum. The crude product thus obtained was purified by column chromatography on 100 g of Kiesel gel using an eluting agent comprising a mixture (20:1 by volume) of methylene chloride and ethyl acetate to provide 590 mg of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].[F:11][C:12]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][NH2:15]>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:15][CH2:14][CH2:13][C:12]([F:20])([F:11])[C:16]([F:19])([F:18])[F:17])=[O:8])[CH3:2]
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(C)C(=O)O
Product: CCOC(=O)C(C)C(=O)NCCC(F)(F)C(F)(F)F

Procedure:
2-Methyl-malonic acid monoethyl ester was coupled with 3,3,4,4,4-pentafluoro-butylamine in analogy to the description in example 73 to yield 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid ethyl ester as colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH:14]([Li])(CC)[CH3:15].C(I)C>C1COCC1>[CH2:1]([C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7])[CH2:14][CH3:15]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: [Li]C(C)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCCc1cccc2c1C(=O)NS2(=O)=O
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 28A 10 g (0.051 mol) of 4-methylsaccharin was reacted with 86 ml (0.10 mol) of a 1.18M solution of s-butyl lithium in THF and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin, which on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide afforded a 65% yield of 2-phenyl-thiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)C1CCOCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCOCC3)nc12

Procedure:
From tetrahydro-pyran-4-yl-carboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][N:11]([CH2:36][CH2:35][N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[C:25]([F:24])[CH:34]=3)[CH:29]=[CH:30][C:31]2=[O:38])[CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To cis-1,1-dimethylethyl [((3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-piperidinyl)methyl]carbamate (350 mg; 1.0 mmol) in MeOH (2 ml) and CHCl3 (8 ml) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 2(d) (200 mg; 1.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 8 hours. Na(OAc)3BH (530 mg; 2.5 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (415 mg; 78%) as a colorless oil.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S-:18].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:17][S:18][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (3.13 g, 9.23 mmol) in DMF (50 mL) was added sodium thiomethoxide (661 mg, 10.4 mmol) in one portion. The reaction was stirred for 3 days. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (4 times), dried (MgSO4) and concentrated to provide the title compound of step B (2.37 g, 9.20 mmol, 99%, approximately 93% pure, used without further purification). 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.13 (m, 2H), 1.42 (s, 9H), 1.48-1.55 (m, 3H), 1.63 (d, J=12.5 Hz, 2H), 2.07 (s, 3H), 2.45-2.53 (m, 2H), 2.65 (td, J=12.8, 2.6 Hz, 2H), 4.02-4.09 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([C:30]3[C:31]4[N:32]([CH:49]=[CH:50][N:51]=4)[CH:33]=[C:34]([Sn](CCCC)(CCCC)CCCC)[N:35]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[CH2:13][CH2:12][O:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:52]([O:56][C:57]([N:59]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:60]1[CH:65]=[N:64][CH:63]=[C:62](Br)[N:61]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>>[C:52]([O:56][C:57]([N:59]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:60]1[N:61]=[C:62]([C:34]2[N:35]=[C:30]([N:22]([C:19]3[CH:20]=[CH:21][C:16]([N:14]4[CH2:13][CH2:12][O:11][C@@H:10]([CH2:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15]4)=[CH:17][CH:18]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:31]3[N:32]([CH:49]=[CH:50][N:51]=3)[CH:33]=2)[CH:63]=[N:64][CH:65]=1)=[O:58])([CH3:55])([CH3:54])[CH3:53]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2ccnc2c(N(C(=O)OC(C)(C)C)c2ccc(N3CCO[C@@H](COC(=O)OC(C)(C)C)C3)cc2)n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(Br)n1
Product: CC(C)(C)OC(=O)OC[C@H]1CN(c2ccc(N(C(=O)OC(C)(C)C)c3nc(-c4cncc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n4)cn4ccnc34)cc2)CCO1

Procedure:
(R)-tert-Butyl (4-(2-(((tert-butoxycarbonyl)oxy)methyl)morpholino)phenyl)(6-(tributylstannyl)imidazo[1,2-a]pyrazin-8-yl)carbamate XIX was reacted with 2-Bis(tert-butoxycarbonyl)amino-6-bromopyrazine XIV according to the analogous method of CHEMISTRY A as described in Example 2 to provide the desired compound (R)-tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(2-(((tert-butoxycarbonyl)oxy)methyl)morpholino)phenyl)carbamate XX.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2([O:32][CH2:31][CH2:30][O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:29]
Reactant: OCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(3'-Chloropropoxy)-3α-hydroxy-5α-pregnane-11,20-dione (470 mg.) was added to a mixture of ethylene glycol (4 ml.), toluene-p-sulphonic acid (3 mg.) and benzene (50 ml.). The vigorously stirred mixture was refluxed under a Dean and Stark head for 17 hours. The cooled mixture was neutralised with sodium bicarbonate solution, ether (50 ml.) added and the organic mixture was washed with water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to give the title compound (520 mg.) as a white foam, [α]D + 37.5° (c 1.03).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(CC)CC>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:28][CH2:27]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 18.9 mg (0.07 mmol) 2-Morpholin-4-yl-5-nitro-benzoyl chloride, 16.5 mg (0.084 mmol) 1-(2-Chloro-phenyl)-piperazine and 34 ul (0.245 mmol) NEt3 in 2 ml DCM was stirred at room temperature for 16 h. After evaporation of the volatiles the residue was taken up in 2 ml CH3CN/MeOH/HCOOH 2/2/1 and subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 23.2 mg (77%) of the title compound. MS (m/e): 431.2 (MH+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
Under an nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 2.59 g (13.5 mmol) of EDC and 1.22 g (9.0 mmol) of HOBT are dissolved in 20 ml of DMF. After 15 min, 3.79 ml (27 mmol) of TEA are added and then a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 41 ml of DMF is added dropwise. After 3 hours the reaction mixture is concentrated by evaporation. The resulting oil is dissolved in ethyl acetate and a small amount of THF and washed with 2×water, sat. NaHCO3 solution, 2×water and brine. The aqueous phases are extracted with ethyl acetate; the combined organic phases are dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; methylene chloride/THF 5:1) and crystallisation from ethyl acetate/DIPE yield the title compound: HPLC20-100: tRet=16.0; FAB MS (M+H)+=640.