Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:12][C:11]([CH:8]1[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCNCC1
Reaction time: 8 h
Yield: 97.25 %

Procedure:
Thionyl chloride (5.42 g, 46 mmol) was added to a cold (0-4° C.) stirred solution piperidine-4-carboxylic acid (5 g, 38.7 mmol) in benzyl alcohol (150 mL) and stirring was continued overnight. Benzyl alcohol was removed by stirring with hexane, ether and decanting the solvent, dried to afford 8.26 g (97.25% yield) of piperidine-4-carboxylic acid benzyl ester. LCMS Purity: 94.8%.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:38])[CH3:37].ClCCl>C1COCC1>[CH2:36]([NH:38][C:28]([NH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])=[O:34])[CH3:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)NC1(c2ccc(C(C)C)cc2OC)C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.52 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and was dissolved in anhydrous THF (10 ml) and was added ethylamine (2.0M in methanol, 2 mL, 400 mmol) and was stirred for 2 hrs. Concentrated reaction mixture was added dichloromethane to afford the title compound (450 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCO)C1c1ccccc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
To a solution of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (2.5 g) in acetone (30 ml) was added 6 N hydrochloric acid (1 ml) and treated in a substantially similar manner to those of Example 2-6) to give a viscous oil (2.10 g) of 2-hydroxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine -3-carboxylate.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH2:12][OH:13].[C:21]([N:25]=[C:26]=[S:27])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[C:21]([NH:25][C:26]([NH:10][CH:11]([CH2:12][OH:13])[CH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[S:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: NC(CO)Cc1cnccn1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)Cc1cnccn1
Temperature: 50 °C

Procedure:
11.2 cm3 of triethylamine are added with stirring to a solution of 7.91 g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride in 80 cm3 of ethanol, followed by addition of 7.2 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C., taken up in 100 cm3 of water and extracted with dichloromethane. The organic phases are combined, washed with 50 cm3 of water, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. 7.2 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]thiourea are obtained in the form of a colourless paste [mass spectrum: DCI m/z=269 MH+]
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]([N:32]1[CH2:35][C:34](=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][O:48][Si](C(C)(C)C)(C)C)[CH:42]=2)[S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1.C(OCC)(=O)C>[CH:19]([N:32]1[CH2:33][C:34](=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][OH:48])[CH:42]=2)[S:37]([CH3:40])(=[O:39])=[O:38])[CH2:35]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=C2CN(C(c3ccccc3)c3ccccc3)C2)S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(CO)c1
Reaction time: 3 h
Yield: 57.8 %

Procedure:
4 cm3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution, cooled to 5° C., of 1.1 g 1-benzhydryl-3-([3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}azetidine in 10 cm3 of tetrahydrofuran. The mixture is stirred for 3 hours at a temperature close to 20° C. and then taken up in 100 cm3 of ethyl acetate and twice 50 cm3 of water. The organic phase is decanted off, extracted, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane and ethanol (95/5 by volume) as eluent and collecting 60 cm3 fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.5 g of 1-benzhydryl-3-[(3-hydroxymethylphenyl) (methylsulfonyl)methylene]azetidine is obtained in the form of a white solid melting at 152° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J=5 Hz, OCH2), 4.75 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (8H, m. 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(CC)CC.[CH2:29]([O:31][C:32]([C:34]1[C:39]([O:40][CH2:41][CH3:42])=[C:38]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[N:37]=[C:36]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:56]([NH:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]([OH:67])=O)=[CH:61][CH:60]=3)=[O:57])=[CH:51][CH:50]=2)[N:35]=1)=[O:33])[CH3:30]>CN(C=O)C>[CH2:29]([O:31][C:32]([C:34]1[C:39]([O:40][CH2:41][CH3:42])=[C:38]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[N:37]=[C:36]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:56]([NH:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]([N:19]4[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]4)=[O:67])=[CH:61][CH:60]=3)=[O:57])=[CH:51][CH:50]=2)[N:35]=1)=[O:33])[CH3:30]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)O)cc3)cc2)nc(N2CCOCC2)c1OCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)N4CCN(C)CC4)cc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 30 %

Procedure:
EDC (53.7 mg, 1.5 eq.), HOBT (42.9 mg, 1.5 eq.), 1-methyl-piperazine (0.03 ml, 1.5 eq.) and Et3N (0.053 ml, 2.0 eq.) were added to a stirred solution of 2-{4-[3-(4-carboxy-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (80 mg, 1 eq.) in dry DMF (2 ml) and the mixture reacted overnight at r.t. The mixture was quenched with H2O, extracted with EA, and washed with brine. The crude was purified by chromatography to give a product (34.5 mg, 30%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8](Br)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:24][O:25][C:26](=[O:32])[C@@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28]>>[CH3:24][O:25][C:26](=[O:32])[C@H:27]([NH:28][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:7]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)=[O:4])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: C1CCNC1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Product: COC(=O)[C@H](NC(=O)c1cnc(N2CCCC2)c(-c2ccc(F)cc2)n1)C(C)C

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 146, using 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester, pyrrolidine and (R)-valine methyl ester as starting materials, LC at 215 nm; Rt 2.43: 100%, m/z (ES+): 401.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:14](=[S:16])=[S:15].[H-].[Na+].[CH3:19]I>CS(C)=O>[CH2:12]([O:11][C:9]([C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:15][C:14]=1[S:16][CH3:19])=[O:10])[CH3:13]
Reactant: S=C=S
Reactant: CI
Reactant: CCOC(=O)Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(SC)sc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (8.0 g, 40.0 mmol) and carbon disulfide (3.18 g, 42.0 mmol) in DMSO (100 mL) was added sodium hydride portionwise (2.4 g, 60.0 mmol). After 60 minutes stirring at room temperature the mixture was heated at 80° C. for 2 hours. After this time the reaction mixture was allowed to cool to room temperature and methyl iodide (7.6 g, 54.0 mmol) added. After 18 hours ice (50 mL) was added and a yellow precipitate formed which was isolated via filtration to give the title compound as a grey solid (7.95 g, 78%). δH (DMSO-d6) 8.60 (1H, dd, J 1.6, 8.2 Hz), 8.46, (1H, dd, J 1.6, 4.6 Hz), 7.35 (1H, dd, J 4.6, 8.2 Hz), 4.48 (2H, q, J=7.1 Hz), 2.71, (3H, s), 1.49 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30]1([CH2:36][CH:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:37]([OH:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 g (70.6 mmol) dibenzylamino-acetic acid ethyl ester in 240 ml tetrahydrofuran was stirred at −78° C. with 38.8 ml (77.6 mmol) lithium diisopropylamide (2M in heptane) for 30 minutes. 17.4 ml (77.6 mmol) phenylacetaldehyde were added and stirring was continued overnight. The mixture was allowed to warm to room temperature, water was added and most of the organic solvent was removed by distillation. About 20 g citric acid were dissolved in the aqueous residue. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/5 yielded as first eluting fraction 5.4 g (19%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100) and as second eluting fraction 4.1 g (15%) racemic (2R,3R and 2S,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester, MS m/e (%): 404.3 (M+H+, 100).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:36])[CH:26]=3)[N:22]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:19]2=[N:20][CH:21]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>O1CCOCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[S:54])[NH:14][CH2:15][C:16]1[N:17]=[C:18]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:36])[CH:26]=3)[N:22]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:19]2=[N:20][CH:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=S)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 85 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A flask was charged with 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.100 g, 0.157 mmol) and 1,4-dioxane (5 mL). Lawesson's Reagent (0.095 g, 0.235 mmol) was added and the mixture was stirred at about 85° C. for about 1 h. The mixture was cooled to rt, concentrated in vacuo and the residue was partitioned with EtOAc (10 mL) and saturated aqueous NaHCO3 (7 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanethioamide (0.103 g, 100%): LC/MS (Table 2, Method b) Rf=3.84 min; MS m/z 654 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(#N)C>[C:12]([O:16][C:17](=[O:18])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: COc1cc(CN)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-3-methoxybenzylamine (1.0 g, 5.27 mmol) in acetonitrile (30 mL) was added tert-butyldicarbonate (1.27 g, 5.80 mmol) and di-isopropylethylamine (1.84 mL, 10.54 mmol). The reaction was stirred at room temperature for 16 h before being partitioned between EtOAc (60 mL) and water (30 mL). The aqueous phase was separated and re-extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4, filtered and concentrated. Purification by flash chromatography (40% EtOAc/hexanes) gave tert-Butyl(4-hydroxy-3-methoxybenzyl)carbamate. LCMS 275.9 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
Triethylamine (43 mL, 309 mmol) was added over 2-3 min to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 23.2 g, 103.8 mmol) in dry dichloromethane (260 mL), yielding a heavy precipitate. Dichloromethane (25 mL) was added, followed by N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 30; 19.36 g, 79.8 mmol) in one portion. Dichloromethane (35 mL) was added and the mixture was stirred at 0° C. for 5 min and then heated in an oil bath at 50° C. for 4 h. The mixture was poured into cold water (500 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×300 mL) and the combined organic layers were washed with brine (200 mL), dried (magnesium sulfate), filtered, evaporated, and purified by silica gel chromatography, eluting with 20-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and dried under high vacuum to give N′-(2-chloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (23.4 g, 70%) as a pale foam.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.COCC(O)C.[NH2:61][C:62]1[CH:67]=[CH:66][C:65]([N:68]2[CH2:73][CH2:72][N:71]([CH2:74][C:75]([NH2:77])=[O:76])[CH2:70][CH2:69]2)=[C:64]([F:78])[CH:63]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:61][C:62]4[CH:67]=[CH:66][C:65]([N:68]5[CH2:73][CH2:72][N:71]([CH2:74][C:75]([NH2:77])=[O:76])[CH2:70][CH2:69]5)=[C:64]([F:78])[CH:63]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)CN1CCN(c2ccc(N)cc2F)CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCN(CC(N)=O)CC5)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.092 g, 0.26 mmol), N-Phenylbis(trifluoromethanesulphonimide) (0.112 g, 0.314 mmol), N,N-Diisopropylethylamine (0.139 mL, 0.797 mmol) and 1-Methoxy-2-propanol (4.0 mL, 41 mmol) were combined in a tube and stirred at room temperature for 18 hours. 2-[4-(4-Amino-2-fluoro-phenyl)-piperazin-1-yl]-acetamide (0.087 g, 0.34 mmol) was added and the reaction was stirred at room temperature for 4 days to yield an orange solid, 2-(4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-fluoro-phenyl}-piperazin-1-yl)-acetamide; compound with 2 trifluoroacetic acids (35 mg, 16%). LCMS: m/z=581.25 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 8.33 (d, 1H, J=7.9 Hz), 7.95 (s, 1H), 7.80 (d, 1H, J=7.8 Hz), 7.66 (m, 2H), 7.54 (m, 3H), 7.14 (d, 1H, J=4.7 Hz), 7.07 (m, 1H), 6.96 (d, 1H, J=4.7 Hz), 3.95 (s, 2H), 3.5 (m, 2H), 3.31 (m, 4H), 3.09 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].[Cl-].[Na+]>O1CCCC1.O>[C:16]([C:18]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:26]=2)[CH2:19][CH2:20][C:21](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CCC(=C3SCCCS3)CC2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 272 %

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0°C. under an argon atmosphere was added rapidly n-butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78°C. and a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=3[Cl:34])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)c(Cl)c1
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (4.4 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, 1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene (250 mg, 0.882 mmol) was added dropwise. The reaction mixture was stirred for 18 hours. Additional sodium tert-butoxide (0.5 eq) was added and the reaction mixture was stirred for an additional 18 hours. The reaction mixture was subsequently diluted with ethyl acetate and was washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted with an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (143 mg, 37%). ESI-MS m/z [M+H]+ calc'd for C17H18Cl2N4O3S, 430.3. found 431.3.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][SH:25].[OH-:26].[K+]>C(O)C>[NH:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:18])[CH2:16][CH2:17][S:19][CH2:20][CH2:21][S:22][CH2:23][CH2:24][S:25][CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Nc1ccc(Nc2ccccc2)cc1
Reactant: [OH-]
Reactant: SCCSCCS
Agent: [K+]
Solvent: CCO
Product: O=C(CCSCCSCCSCCC(=O)Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 200 grams of N-(4-anilinophenyl)acrylamide in 2450 milliliters of ethanol was added 64.8 grams of 2-mercaptoethyl sulfide. A solution of 5 grams of potassium hydroxide in 50 milliliters of ethanol was then added at 20°C. Within 5 minutes the temperature began to rise, reaching a maximum of 31°C. after about 15 minutes. As the temperature began to rise, product began to precipitate. The reaction mixture was stirred for 1 hour and the solid product was then filtered off and allowed to dry. There was obtained 231.7 grams (87.5 percent of theory) of product which melted at 195.5° to 197.5°C.