Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([NH:8][C:9]([C:11]1[CH:35]=[CH:34][C:14]2[N:15]([CH3:33])[C:16]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[CH2:6][OH:7])C.[OH-].[Li+]>>[OH:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]1[CH:35]=[CH:34][C:14]2[N:15]([CH3:33])[C:16]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)[C@H](CO)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N[C@@H](CO)C(=O)O)ccc21
Yield: 80.3 %

Procedure:
(S)-3-Hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (152 mg) was prepared by following General Procedure E starting from (S)-3-hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid ethyl ester (200 mg) and lithium hydroxide (64 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1.O1CCC(OC2N=CC(C(OCC)=O)=CC=2)CC1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:9]2[N:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CN1CCC(O)C1
Agent: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Product: CCOC(=O)c1ccc(OC2CCN(C)C2)nc1
Yield: 24.5 %

Procedure:
Ethyl 6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate was prepared from 1-methylpyrrolidin-3-ol (0.161 g, 1.59 mmol) and ethyl 6-chloronicotinate (0.269 g, 1.45 mmol) according to the method described for Intermediate 236. The crude material was purified by FCC, eluting with a gradient of 0-20% MeOH in EtOAc to afford the title compound as a colourless oil (0.089 g, 25%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.82 (1H, m), 8.13 (1H, dt), 6.74 (1H, m), 5.43 (1H, m), 4.39 (2H, dq), 2.82 (3H, m), 2.40 (3H, s), 2.39 (2H, m), 2.04 (1H, m) and 1.40 (3H, dt).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][S:8]([CH2:11][CH2:12]Cl)(=[O:10])=[O:9])(=[O:6])=[O:5].[N+](C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O)([O-])=O.C(N(CC)CC)C>CC(C)=O>[CH:11]([S:8]([CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])(=[O:10])=[O:9])=[CH2:12]
Reactant: O=S(=O)(CCCl)CS(=O)(=O)CCCl
Agent: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CS(=O)(=O)CS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a well stirred solution of 53.84 g of bis-(2-chloroethylsulfonyl)methane in 300 ml of acetone containing 0.9 g of 3,5-dinitrobenzoic acid, was added dropwise at 20°-25° C. a solution of 40.48 g of triethylamine in 50 ml of acetone containing 0.15 g of 3,5-dinitrobenzoic acid. The reaction was stirred for 1 hour at 25° C. then cooled to -30° C. and filtered to remove triethylamine hydrochloride. The filtrate was evaporated to dryness on a rotary evaporator at 40° C. and water aspirator pressure. The residue was recrystallized from methanol containing 0.3 percent (wt/vol) of 3,5-dinitrobenzoic acid, to give 29.3 g (75 percent) of colorless crystalline bis(vinylsulfonyl)methane of m.p. 59°-61° C. This material readily dissolved in water to give a 2 percent by weight solution with no insoluble material present.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16](C3C=CC=C(Cl)C=3F)[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14](CC(C)(C)CCN)[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.C(Cl)(=O)C.O>O1CCCC1>[CH3:1][C:2]1([CH3:42])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH2:16][C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH2:14][NH:13]2)=[O:11])[CH2:4][O:3]1
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CCNC(=O)C2CC(C#N)(c3ccc(Cl)cc3F)CN2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (60 mg, 0.096 mmol) prepared in Example 121a and triethylamine (0.033 mL, 0.24 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (0.08 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 30 min, then water was added. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (2% MeOH in EtOAc) to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a off white gum (60 mg, 94%)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[NH:17]1)=[O:36]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: N#CC1(c2ccc(Cl)cc2)C(CC2CCCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)C(CC2CCCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 36 %

Procedure:
In a manner similar to the method described in Example 3b, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 34c (0.4 g, 0.71 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.6 g, 4.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.14 g, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:32][C@H:33]1[O:38][C@@H:37]([CH3:39])[CH2:36][NH:35][CH2:34]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[F:29][C:27]1([F:30])[CH2:28][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:6]5[CH:7]=[C:2]([N:35]6[CH2:34][C@@H:33]([CH3:32])[O:38][C@@H:37]([CH3:39])[CH2:36]6)[CH:3]=[CH:4][C:5]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:26]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(N3C[C@@H](C)O[C@@H](C)C3)cn12
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42h) (25 mg, 0.051 mmol), cis-2,6-dimethylmorpholine (9 mg, 0.077 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.003 mmol), and sodium t-butoxide (10 mg, 0.102 mmol) in anhydrous dioxane (1 mL) was heated in the microwave at 125° C. for 25 minutes. The reaction was cooled to room temperature and filtered through a plug of celite. The solvent was concentrated and the crude product was purified by reverse phase preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-((2S,6R)-2,6-dimethylmorpholino)imidazo[1,2-a]pyridine-3-carboxamide (F96). 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.95 (d, J=1.6 Hz, 1H), 8.64 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.50 (d, J=8.0 Hz, 1H), 3.91-3.86 (m, 1H), 3.76-3.71 (m, 2H), 3.54-3.51 (m, 2H), 3.23-3.03 (m, 4H), 2.36 (s, 3H), 2.31-2.25 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H). MS m/z 522.22 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1/[CH:11]=N/C(C(C)C)C(C)C)[CH3:2].[OH-:20].[Na+]>C1COCC1.Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH:11]=[O:20])[CH3:2]
Reactant: CCc1cccc(CC)c1/C=N/C(C(C)C)C(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1C=O
Temperature: 25 °C

Procedure:
A solution of 15.6 g (E)-[1-(2,6-diethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine in 60 ml THF and 120 ml 4N HCl was heated to reflux for 2 hours then cooled to ambient temperature and poured onto a 1N NaOH solution. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with a heptane/ethyl acetate gradient as eluent: 8.35 g 2,6-diethyl-benzaldehyde as light yellow oil: MS (EI): 162.1 (M+., 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].CN(C)C1C=CC=CC=1.CP(Cl)(CCCCCCCC)=O.P(Cl)(Cl)(Cl)(Cl)Cl.N=O>C(Cl)Cl.C(O)CCC>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCCCCCCCP(C)(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N=O
Solvent: CCCCO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: -25 °C

Procedure:
To a suspension of 14.9 g of penicillin-G-potassium (= 40 mmols) in 60 ml of absolute methylene chloride 10 ml of N,N-dimethylaniline and 8.42 g (= 40 mmols) of methyl-n-octylphosphinic acid chloride were added successively while stirring. After an hour at 0°C the reaction mixture was cooled to -25°C and 9.0 g (= 43 mmols) of phosphorus pentachloride were introduced. After an hour at -25°C, 60 ml of n-butanol and 2 ml of N,N-dimethylaniline were introduced and by after-stirring for an hour at -25°C the iminoether was formed. Then, hydrolysis followed in the manner described in Example 1. 7.47 g (= 88.5 % of the theory) of 6-aminopenicillanic acid having a melting point of 195°C (decomposition) were isolated in the form of colorless crystals, the identity of which was examined in an analogous manner as described in Example 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:8]C)[P:4](=[O:7])([NH2:6])[NH2:5])C.[Cl-].[NH4+].[CH3:12][N:13]([CH3:18])[P:14]([Cl:17])([Cl:16])=[O:15].N.CNC.P(Cl)(Cl)(Cl)=O>CCOCC>[CH3:12][N:13]([CH3:18])[P:14]([Cl:17])([Cl:16])=[O:15].[CH3:1][N:3]([CH3:8])[P:4](=[O:7])([NH2:6])[NH2:5]
Reactant: CCN(CC)P(N)(N)=O
Agent: CN(C)P(=O)(Cl)Cl
Agent: CNC
Agent: N
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)P(N)(N)=O
Temperature: 105 °C

Procedure:
Using the procedure described in M. Goehring and K. Niedenzu, Chem. Ber. 89, pp 1768-1771 (1956), 1300-1400 grams of a material containing 53.5% (by weight) of N,N-diethylphosphoric triamide and 46.5% (by weight) of ammonium chloride was prepared by reacting 1035 g of N,N-dimethylphosphoramidic dichloride and ammonia in ether at 0° C. The N,N-dimethylphosphoramidic dichloride was prepared by adding 425 g (9.45 mol) of dimethylamine to 4000 mL (6580 g, 42.7 mol) of phosphorus oxychloride at 0°-10° C., heating the reaction mixture at reflux (105° C.) for 18 h, and distilling the products at reduced pressure (31P NMR (CDCl3): δ 17.7 ppm). Pure N,N-dimethylphosphoric triamide can be obtained by extracting the crude material with chloroform, evaporating the chloroform, and recrystallizing the residue from acetone/chloroform. For example, extraction of 130 g of crude material with 1300 mL of hot chloroform provided 30 g of pure material, mp 128.5°-131° C. (lit. 119° C.), after recrystallization
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(F)ccc2C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a cooled (0° C.), stirred solution of 528 mg (1.44 mmol) of 3-[3-(5-fluoro-2-methylphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 527 μL (3.02 mmol) of N,N-diisopropylethylamine and 307 μL (4.32 mmol) of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 459 mg (2.88 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 16 h. The mixture was then poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated. The resulting material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichloromethane to afford 320 mg (61%) of the title compound as a colorless syrup: Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H17FO5S: 375.1 (M+Na). Found: 375.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:3]=1.[CH2:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH:22]=[CH2:23]>CS(C)=O.O>[CH2:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:3]=2)[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2cc(Cl)ncn2)cc1
Reactant: C=CCN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: C=CCN1CCN(c2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ncn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
430 mg (1.38 mmol) of N-(6-chloropyrimidin-4-yl)-4-isopropylbenzenesulfonamide from Example 18.1 were dissolved in 3 ml of dimethyl sulfoxide, after which 1.74 g (13.79 mmol) of N-allylpiperazine were added and the mixture was stirred overnight. Subsequently, the reaction mixture was stirred at 100° C., in a microwave oven, for 45 minutes. After the reaction mixture had cooled down to room temperature, it was diluted with 50 ml of water. After that, the aqueous reaction mixture was extracted with 50 ml of ethyl acetate and the precipitate was filtered off with suction, with 190 mg (34% of theory) of the title compound being obtained.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])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.CS(Cl)(=O)=O>C(Cl)Cl>[C:8]([N:3]1[CH2:6][CH2:7]1)([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
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
Amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 mL) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 mL) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high vacuum. To a suspension of the HC1 salt in CH2Cl2 (50 mL) at 0° C. was added triethylamine (3.55 mL, 25.5 mmol) followed by the addition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture was stirred at 0° C. for 1 h and then was warmed to room temperature stirring for 2 h. The reaction was cooled to 0° C., triethylamine (3.6 mL, 25.5 mmol) was added and methane sulfonyl chloride (0.97 mL, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0° C. and for 22 h at room temperature. The reaction was evaporated and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The organic phase was washed with water (200 mL) and the combined aqueous phases were extracted with diethyl ether (200 mL). The combined organic extracts were washed with water (100 mL), saturated NaCl (200 mL) and were dried (Na2SO4), filtered, and evaporated. The crude product was purified on silica gel (1/1-hexane/CH2Cl2) to afford N-trityl aziridine 183 (3.84 g, 86%) as a white foam: 1H NMR (CDCl3) δ 7.4-7.23 (m, 16H), 4.32 (m, 1H), 3.81 (s, 3H), 3.06 (dt, 1H, J=1.8, 17.1), 2.94-2.86 (m, 1H), 2.12 (m, 1H), 1.85 (t, 1H, J=5.0).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH:40]4[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC(C)(C)OC(=O)N1CC(CI)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Yield: 82.1 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH:11]=2)=[CH:2]1.[ClH:19]>CCOC(C)=O.O>[ClH:19].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:11]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccsc2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C1=C(c2ccsc2)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-thienyl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg) in EtOAc (1.7 ml) and water (0.085 ml) was added 4 N hydrogen chloride in EtOAc (1.7 ml) and the mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to give 4-(3-thienyl)-1,2,3,6-tetrahydropyridine hydrochloride (120 mg) as a dark gray powder. The obtained crude product was used in next reaction without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C3CCCCO3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.O1CCOCC1>[OH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:8]([C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(I)cc2)c(C)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(I)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of N-(4-iodo-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.506 g, 0.86 mmol) in 5 mL tetrahydrofuran was added HCl (5.35 mL of a 4.0 M solution in 1,4-dioxane, 21.4 mmol) and triethylsilane (1.37 mL, 8.56 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was separated and concentrated. Medium pressure silica gel chromatography of the residue (methylene chloride) afforded 0.36 g (83%) of the title compound of Step C.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 49F (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1H) 0.78 (m, 10H) 1.59 (s, 3H) 2.08 (m, 1H) 2.23 (td, J=12.78, 4.60 Hz, 1H) 7.07 (m, 2H) 7.53 (m, 2H) 7.77 (m, 2H) 8.16 (d, J=7.72 Hz, 1H) 13.58 (s, 1H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH:10][OH:11])=[CH:8][C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[CH:13]([O-])([O-])OCC>CN(C)C=O>[CH3:12][N:5]1[C:6](=[O:7])[C:8]2=[CH:13][O:11][N:10]=[C:9]2[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCOC([O-])[O-]
Reactant: Cn1c(NO)cc(=O)n(C)c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2conc2n(C)c1=O

Procedure:
A mixture of 2 g of 1,3-dimethyl-6-hydroxyamino-uracil, 20 ml of dimethylformamide and 20 ml of ethyl orthoformate is boiled at 160° C. for 1 hour, after which the solvent is distilled off. To the residue is added ethanol and the resultant crystals are collected by filtration. As recrystallized from hot water, 1.0 g of the captioned compound is obtained as colorless prisms, melting point: 170°-171° C.