Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:35])([F:34])[C:19]1[N:24]=[C:23]([N:25]2[CH2:29][C@@H:28]3[C@@H:30]([NH2:33])[CH2:31][CH2:32][C@@H:27]3[CH2:26]2)[CH:22]=[CH:21][CH:20]=1.[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH3:36][C:11]([CH3:12])([CH3:13])[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14](=[O:16])[NH:33][C@@H:30]1[C@@H:28]2[C@@H:27]([CH2:26][N:25]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:18]([F:17])([F:34])[F:35])[N:24]=3)[CH2:29]2)[CH2:32][CH2:31]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-L-neopentylglycine for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.78 (s, 1H), 7.45 (s, 1H), 7.05 (s, 1H), 6.91 (d, J=7.3, 1H), 6.47 (d, J=8.6, 1H), 4.53 (td, J=8.3, 4.7, 1H), 4.28-4.19 (m, 1H), 3.67-3.56 (m, 2H), 3.52 (dd, J=10.9, 7.9, 1H), 3.27 (dd, J=11.0, 3.7, 1H), 2.76-2.66 (m, 2H), 2.13 (dd, J=14.3, 4.6, 1H), 2.06 (dt, J=12.8, 6.4, 1H), 1.91 (td, J=13.3, 7.9, 1H), 1.73 (dd, J=14.3, 8.0, 1H), 1.62 (dq, J=15.1, 7.7, 1H), 1.50 (s, 9H), 1.37 (qd, J=7.9, 4.9, 1H), 1.00 (s, 9H); MS (ESI+) m/z 499 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (98.3 mmol) of 9-phenylanthracene was put into a 1-L three-neck flask, and 300 mL of carbon tetrachloride was added thereto. A solution in which 15.6 g (98.3 mmol) of bromine was dissolved in 40 mL of carbon tetrachloride was dropped in the reaction solution at the room temperature. After the dropping, the reaction solution was stirred at the room temperature for 1 hour. Thereafter, the reaction is completed by adding a sodium thiosulfate aqueous solution, and the solution was further stirred for 1 hour. An organic layer of the reaction mixture was washed with aqueous sodium hydroxide (2.0 mol/L) and saturated saline and dried with magnesium sulfate. This mixture was filtrated naturally, and the filtrate was condensed to obtain a solid. The solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was concentrated to obtain a solid, and the solid was recrystallized with a mixture solution of dichloromethane and hexane, whereby 27.8 g of a light yellow powdery solid that was a target matter was obtained with the yield of 85%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:25]1([O:24][C:22](=[O:23])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one intermediate D (0.05 g, 0.176 mmol), phenyl chloroformate (27.5 mg, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, then the crude product was purified using preparative reverse-phase HPLC to provide (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamic acid phenyl ester. MS calcd. for C24H18ClN5O [(M+H)+] 405.1, obsd. 404.9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[Cl:14])=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].CC([O-])=O.[Na+]>>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[C:3]1[CH:2]=[N:22][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:21]=1
Reactant: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cnc3ccccc3n2)c1
Yield: 60 %

Procedure:
Procedure B was performed with 2-bromo-2′chloro-5′-nitroacetophenone (14.16 g, 50 mmol), 1,2-phenylenediamine (13.1 g, 120 mmol) and NaOAc (12.4, 150 mmol) to give the desired 2-(2-chloro-5-nitro-phenyl)-quinoxaline (8.6 g, 30 mmol).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]([CH2:21][CH2:22][OH:23])([CH2:19][OH:20])[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(Cl)(Cl)Cl>[CH3:36][S:37]([O:20][CH2:19][C:17]1([CH2:21][CH2:22][O:23][S:37]([CH3:36])(=[O:39])=[O:38])[O:16][N:15]=[C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]3[CH:26]=[N:25][N:24]([CH2:27][CH3:28])[C:10]3=[N:11][CH:12]=2)[CH2:18]1)(=[O:39])=[O:38]
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CCO)C3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CCOS(C)(=O)=O)(COS(C)(=O)=O)C3)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl}ethanol (150 mg, 0.00038 mole) (example 11) was taken in a mixture of dichloromethane and chloroform (10 ml: 10 ml). At 0° C., triethylamine (0.153 g, 0.001513 mole) and methane sulphonyl chloride (0.173 g, 0.001513 mole) were added. The reaction mixture was stirred at 0° C. for about 2 h. The mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Br:11][C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>CCOCC.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:11][C:12]1[C:13]([NH:19][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: COc1ccc(Cl)cc1I
Reactant: Cc1cnc(N)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1Nc1ncc(C)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
In a oven dried 50 mL round bottom flask were sequentially added 4-chloro-2-iodo-1-methoxybenzene (1.13 g, 4.2 mmol), 3-bromo-5-methylpyridin-2-amine (945 mg, 5.05 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), xantphos (146 mg, 0.25 mmol) and NatBuO (605 mg, 6.3 mmol) at room temperature. The solid materials were kept under vacuum for 5 min. and then refilled with nitrogen. This process was repeated thrice before adding dry, degassed dioxane (10 mL). The heterogeneous mixture was stirred at room temperature for 15 min. and then at 100° C. for 1 h. Finally upon completion of the reaction, it was diluted with ether and filtered through a small pad of silica gel with several washings. All the washings and filtrate concentrated in vacuum and the crude residue was further purified by flash chromatography to provide title compound (1.16 g, 84%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.26 (s, 3H) 3.94 (s, 3H) 6.81 (d, J=8.59 Hz, 1H) 6.93 (dd, J=8.72, 2.65 Hz, 1H) 7.65 (d, J=2.02 Hz, 1H) 7.77 (br. s, 1H) 8.07 (d, J=1.26 Hz, 1H) 8.58 (d, J=2.27 Hz, 1H). [M+H] calc'd for C13H13ClN2O, 326.98; found 327.2.
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=O)C.[C:14](Cl)(=O)C.C(=O)(O)[O-].[Na+]>CO>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]#[C:6][CH2:5][OH:4]
Reactant: CC(=O)OCC#CCCCC(=O)O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC#CCO
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude acid 29 (6.333 g) was treated with a 1% solution of acetyl chloride in methanol (60 mL). After 16 h, sodium bicarbonate (1.966 g, 23.4 mmol) was added. The mixture was dried (MgSO4), filtered through celite and evaporated in vacuo. Purification by flash chromatography on silica gel (30-40% ethyl acetate/hexanes) gave 7-Hydroxy-hept-5-ynoic acid methyl ester 30 (3.022 g, 19.3 mmol, 92% from 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][N:24]=1>>[ClH:29].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20][C:27]3[N:26]=[CH:25][N:24]=[C:23]([NH2:22])[CH:28]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Product: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3Sc3cc(N)ncn3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C20H15FN6S, 390.11; m/z found, 391.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.29-8.25 (m, 3H), 7.94 (m 1H), 7.82 (d, J=7.4, 1H), 7.74 (m, 1H), 7.67-7.58 (m, 2H), 7.34-7.23 (m, 2H), 5.94 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:6][N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: CN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
9-Methyl-3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (435 mg, 1.62 mmol) was dissolved in dichloromethane (11 mL) and cooled on ice. Trifluoroacetic acid (4 mL) in dichloromethane (5 mL) was added and the reaction mixture was stirred at room temperature for 2 h. Evaporation to dryness, co-evaporation with toluene, ethyl acetate and diethyl ether gave a foam which was dissolved in dichloromethane, and sodium hydroxide (2 N) was added. The aqueous phase was extracted five times with dichloromethane. The combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated to give 214 mg (78%) of 3-methyl-3,9-diaza-spiro[5.5]undecane.
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][C:4]1[C:21]([O:22][CH3:23])=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=O)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].Cl.[NH2:28][OH:29].C(=O)(O)[O-].[Na+].O>CO.C(OCC)(=O)C>[S:1](=[O:26])(=[O:25])([O:3][C:4]1[C:21]([O:22][CH3:23])=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])/[C:13](=[N:28]/[OH:29])/[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: NO
Reactant: COc1cc2c(cc1OS(N)(=O)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OS(N)(=O)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)/C(=N/O)CC[C@@H]12
Yield: 74.9 %

Procedure:
A suspension of 570 mg of 2-methoxy-17-oxo-estra-1,3,5(10)-trien-3-yl sulfamate, 365 mg of hydroxylamine hydrochloride and 441 mg of sodium bicarbonate in 8 ml of methanol was stirred under reflux for one hour. Then, it was mixed with 30 ml each of water and ethyl acetate. After phase separation, the aqueous phase was extracted twice more with 15 ml each of ethyl acetate. The combined organic phases were first washed with 15 ml of 0.5N HCl and then with saturated NaCl solution, dried on sodium sulfate and concentrated by evaporation in a rotary evaporator. The crude product was purified by flash chromatography (toluene/ethyl acetate 3:1). 444 mg (73%) of 2-methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-yl sulfamate (17) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])(=O)OC.O.[NH2:28][NH2:29]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:28][N:29]=[C:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:19]=1
Reactant: COP(=O)(CC(=O)CCC(C)C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC(C)CCc1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (ESI): 259.0 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (5-methyl-2-oxo-hexyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C(O[C:9]1[CH:17]=[CH:16][C:15]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:10]=1[CH:27]=[O:28])C1C=CC=CC=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N#N>ClCCCl>[OH:33][CH2:32][CH2:31][N:30]([CH2:9][C:10]1[C:27]([OH:28])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:29]
Reactant: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#N
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCO)Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
To a solution of 5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.12 mmol, Intermediate 62) in DCE (3 mL) was added N-methyl ethanolamine, 22 mg (0.26 mmol) and sodium triacetoxyborohydride, 80 mg (0.38 mmol) and the mixture was heated in a sealed test tube at 40° C. over night. The solvent was removed at reduced pressure and the residue was dissolved in MeOH (2 mL), 10% Pd/C, 20 mg was added and the mixture was flushed with N2, NH4+HCOO− (50 mg, 0.8 mmol) was added, the reaction mixture was again flushed with N2 and the reaction mixture was stirred at 40° C. over night. The solvent was removed at reduced pressure, the semisolid was taken up between CHCl3/H2O, washed with H2O (×1), brine (×1), dried (MgSO4) and the solvent was removed at reduced pressure. A sample was withdrawn and purified with on a preparative HPLC, method B, to yield 6.3 mg of a colorless oil. MS (ESI+) for C18H20N2O4S m/z 361 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])(C)OC1=O)(=[O:3])[CH3:2].C(O[CH:17]([O:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=CCO)=[CH:22][CH:21]=1)[CH3:18])C.[O:30]1CC[CH2:32][CH2:31]1>>[C:9]([O:8][CH2:7][CH:12]=[CH:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:17][CH2:18][O:30][CH2:31][CH3:32])=[CH:29][CH:28]=1)(=[O:10])[CH2:4][C:1]([CH3:2])=[O:3]
Reactant: CC(=O)C1C(=O)OC(C)(C)OC1=O
Reactant: C1CCOC1
Reactant: CCOC(C)Oc1ccc(C=CCO)cc1
Product: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1

Procedure:
18.6 Grams of 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione and 50 ml tetrahydrofuran solution containing 22.2 g of 4-(1-ethoxyethoxy)cinnamyl alcohol were refluxed for 6 hours. After the reaction was completed, the solvent was removed by evaporation, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:4) to yield 5.8 g of 4-[(1-ethoxy)ethoxy]cinnamyl acetoacetate as in the form of an oily substance.
Reaction SMILES: CN1CCCN(C)C1=O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[CH2:18][S:19]([C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=1)(=[O:21])=[O:20].C([Li])CCC.[I:34]N1C(=O)CCC1=O>C1COCC1>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[C:12]=1[CH:18]([I:34])[S:19]([C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=1)(=[O:20])=[O:21]
Reactant: CC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC1(C)CC(S(=O)(=O)C(I)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) (0.10 ml, 0.83 mmol) and 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydro-isoxazole (0.20 g, 0.69 mmol) were dissolved under nitrogen in THF (7 ml) and cooled to −78° C. n-Butyl lithium (2.5M in hexane) (0.33 ml, 0.83 mmol) was added dropwise. After 30 min at −78° C., N-iodosuccinimide (NIS) (187 mg, 0.83 mmol) was added. The mixture was stirred for 1 hour and allowed to warm slowly to room temperature. The reaction was quenched by addition of aqueous ammonium chloride solution. Extraction was carried out several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) and recrystallised from isopropyl alcohol to give the product (Compound No. 1.25 of Table 27) as a white solid (110 mg, 38% yield).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[K].S(OC)(O[CH3:18])(=O)=O>CC(C)=O>[CH3:7][C:6]1[C:2]([O:1][CH3:18])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[S:4][C:5]=1[CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1sc(C)c(C)c1O
Agent: [K]
Solvent: CC(C)=O
Product: COC(=O)c1sc(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate (Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added anhydrous potassium carbonte (24.5 g, 178 mmol) and the mixture stirred for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was added and the mixture stirred under reflux for 2.5 hours. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated to give crude product which was used in the following preparation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=[N:13][N:7]3[C:6]=2[CH:20]=1.CC[C:23]([O-:25])=[O:24].Cl.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]([C:23]([OH:25])=[O:24])=[N:13][N:7]3[C:6]=2[CH:20]=1
Reactant: Fc1ccc2c(c1)N1N=CC(c3ccccc3)C1CO2
Reactant: CCC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=NN2c3cc(F)ccc3OCC2C1c1ccccc1

Procedure:
A solution of the racemic ester (1-6) (0.5 g, 1.5 mmol) in EtOH (10 mL) was treated with 12N HCl (10 mL) and heated at reflux for 8 h. The reaction was cooled to room temperature and neutralized with 3N NaOH and the mixture extracted with EtOAc (50 mL). The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in MeCN (0.5 mL) and purified by reverse phase HPLC (YMC J-sphere H80 20×50 mm; eluted with 5-95% MeCN/water+0.1% TFA) to provide racemic (3-1). 1H NMR (500 MHz, CDCl3) δ 7.33 (m, 6H), 7.02 (m, 1H), 6.85 (m, 1H), 4.33 (m, 2H), 4.22 (m, 1H), 3.64 (m, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CON(C)[C:13](=[O:27])[CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13](=[O:27])[CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C#N)cc1)C(C)(C)C
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a dried and cleaned 10 L cryo reactor was added 4-bromobenzonitrile (321 g; 1.74 mol; 2.5 eq) and THF (995 mL; 5.0 vol). The stirred mixture was inerted under a nitrogen atmosphere and cooled (Tj −20° C.). To the cooled mixture at Tj −13° C. Turbo Grignard reagent (Turbo Grignard Reagent from Chemetall equal to iPrMgCl/LiCl 14% w/w in THF; 1.81 L; 2.5 eq) was charged under the nitrogen atmosphere while maintaining the temperature below approx −10° C. during 1 h 14 min. The reaction intermediate was left at approx 0° C. for 3 h giving a conversion of >97% (analytical sample quenched with 15% w/w aq NH4Cl). The mixture was cooled to Ti −20° C. and a solution of tert-butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (191 g; 0.70 mol; 1.0 eq) in THF 496 mL; 2.6 vol) was charged to the reactor for 28 min at approx-10° C. to −6° C. (exothermal reaction). The vessel was rinsed with THF (221 mL; 1.3 L), the reaction mixture warmed to 20° C. and left overnight affording a conversion (HPLC) of approx 90%. The mixture was cooled to 0° C. (Tj-10) and a solution of potassium sodium tartrate (Rochelle salt) (153 g; 1.05 eq) in water (10 vol) was drop wise added during 30 min keeping the temperature at 0 to 10° C. giving an orange coloured slurry. Tj was set to 40° C. and stirring was stopped at Ti 30° C. and the phases allowed to separate. The red coloured organic layer was recovered and the yellow slurry-like water phase was extracted twice at Tj 30° C. with iPrOAc (2×1.91 L; 2×10 vol). The organic layers were combined (7.5 L) and washed at Tj 30° C. three times with a brine-water mixture (3+3 vol; 5+5 vol; 3+3 vol). The washed organic layer was concentrated in vacuo at Tj 60° C. to approx 1.5 L volume and diluted (iPrOAc) to 2 L. The product solution was taken to the next step (example 3, method 2) without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl.[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=O)[CH2:12][CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO>[CH:8]1([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:17][NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1nc[nH]n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc[nH]n2)cc1OC1CCCC1

Procedure:
To a stirred solution of 3-amino-1,2,4-triazole (1.5 g, 0.018 mol), 7.5 ml of 1N HCl, and 50 ml of methanol was added 3-cyclopentyloxy-4-methoxybenzaldehyde (3.3 g, 0.015 mol) and sodium cyanoborohydride (0.945 g, 0.015 mol). A precipitate formed slowly and after 20 hours the precipitate was filtered and recrystallized from methanol (135 ml) to give 1.0 g (0.0034 mol. 23%) of the title compound, mp 203-204° C.