Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].Br[CH2:8][CH2:9][CH:10]=[O:11].[OH-].[Na+]>CO>[CH3:1][C:2]([NH:6][CH2:8][CH2:9][CH:10]=[O:11])([CH3:5])[C:3]#[CH:4]
Reactant: C#CC(C)(C)N
Reactant: O=CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CC(C)(C)NCCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylprop-2-ynylamine (1.0 mole), the diethyl acetal of 3-bromopropionaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 3-(1,1-dimethylprop-2-ynylamino)propionaldehyde.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].I[CH3:23]>CN(C=O)C>[CH3:23][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc([N+](=O)[O-])c1)S(=O)(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 114.9 %

Procedure:
A 60% suspension of NaH (0.47 g, 11.75 mmol) was added to a solution of N-(3-nitrophenyl)benzenesulfonamide (2.56 g, 9.20 mmol) and iodomethane (2.61 g, 18.4 mmol) in DMF (50 mL) at room temperature. The yellow solution changed to a bright brown color. After 1.5 h at room temperature, the reaction mixture was quenched with careful addition of water (100 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with saturated NH4Cl, brine, dried (MgSO4) and concentrated to give N-methyl-N-(3-nitrophenyl)benzenesulfonamide (3.09 g). LCMS: (M+MeCN+Na)+=356.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, ddd, J=8.03, 2.26, 1.25 Hz), 7.94 (1H, t, J=2.13 Hz), 7.70-7.76 (1H, m), 7.66 (1H, t, J=8.03 Hz), 7.57-7.62 (3H, m), 7.52-7.56 (2H, m), 3.21 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23]O)[OH:22])[OH:20])[OH:18])[OH:16]>O>[CH2:2]([OH:1])[C@H:3]1[O:4][C@H:11]([O:12][CH2:23][C@H:21]2[O:22][C:15]([OH:16])([CH2:14][OH:13])[C@@H:17]([OH:18])[C@@H:19]2[OH:20])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Specifically, an isomaltooligosaccharide saccharification solution with Bx of 70 to 73 was obtained by adding water to a liquid fructose (HFCS-42, Ingredion Korea) having a fructose content of 42 to 45% (w/w) based on solids and Bx of 75 to 77. To the solution was added a dextrose saccharification enzyme, glucoamylase (AMG, Novozymes Korea), in an amount of 2.0 to 2.5% (w/w) based on the total weight of solids in the saccharification solution at a temperature of 65 to 70° C. and a pH of 4.3 to 4.7, followed by a reaction for 90 to 96 hours. The obtained solution was subject to filtration using diatomite to remove the unreacted materials, decolorization by passing through a column filled with granular active carbon at a temperature of 70 to 75° C., ion purification using a cation exchange resin (PK218, Samyang) and an anion exchange resin (WA30, Samyang), and evaporation to remove moisture to obtain an isomaltulose-containing isomaltooligosaccharide composition with Bx of 75 to 77.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]=1[N+:21]([O-])=O.[N:24](OCCC(C)C)=O>CCO.CCOC(C)=O.[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:21]=[N:24][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1
Reactant: Nc1nc(NCc2ccccn2)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CC(C)CCON=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccccn3)c2n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
A solution of 6-(2-furyl)-5-nitro-N4-(2-pyridylmethyl)pyrimidine-2,4-diamine (270 mg, 0.864 mmol) and 10% Pd/C (92 mg, 0.086 mmol) in EtOH (30 mL) and EtOAc (10 mL) was stirred under an hydrogen atmosphere for 1 h, filtered through Celite and concentrated in vacuo. The resulting yellow oil was dissolved in dioxane (25 mL), treated with isoamyl nitrite (0.109 mL, 0.815 mmol), stirred at 100° C. for 6 h, cooled to room temperature, filtered through Celite, concentrated in vacuo and triturated with Et2O to give the title compound (110 mg, 46%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[CH3:17][NH:18][C:19](SC)=[CH:20][N+:21]([O-:23])=[O:22]>O1CCCC1.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:19]([NH:18][CH3:17])=[CH:20][N+:21]([O-:23])=[O:22])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 60 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
0.7 g of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine and 1.35 g of N-methyl-1-methylthio-2-nitro-1-ethenamine were dissolved in a solvent mixture of tetrahydrofuran (50 ml) with water (3 ml) and stirred at 60° C. for 8 hours. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methanol/dichloromethane) to thereby give 0.14 g of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:15]([C:17]1[O:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:16].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:20]1[O:21][C:17]([CH2:15][CH3:16])=[N:18][N:19]=1)=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CCc1nnc(N)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nnc(NC(=O)c2ccc(C(F)(F)F)nc2Cl)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg (0.887 mmol) of 2-chloro-6-(trifluoromethyl)nicotinic acid and 100 mg (0.887 mmol) of 5-ethyl-1,3,4-oxadiazol-2-amine are dissolved at RT in 8 ml of CH2Cl2. Then 846 mg (1.33 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) are added, the mixture is stirred at RT for one hour and then 0.618 ml (4.43 mmol) of triethylamine, 22 mg (0.177 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at RT for 20 h and then washed twice with 4 ml each time of water, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (prep. HPLC; acetonitrile/water). Yield 80 mg (28%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[S:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C2CCN(c3nnc(C(F)(F)F)s3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole in dimethylsulfoxide at 85° C. in the presence of potassium carbonate. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH2:9][CH:10]=[CH2:11].C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH:9]=[CH:10][CH3:11]
Reactant: C=CCC(=O)C1=C(C)C(=O)CCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC=CC(=O)C1=C(C)C(=O)CCC1(C)C
Yield: 100.2 %

Procedure:
153 g (0.74 mole) of 2,4,4-trimethyl-3-(but-3-en-1-on-1-yl)-cyclohex-2-en-1-one (Ib) were stirred under reflux together with 135 ml of ethyl acetate and 3 g of p-toluenesulfonic acid for 2 hours. When the solution had cooled, 1,000 ml of ether were added to it, the mixture was washed with water and with saturated sodium bicarbonate solution and dried with sodium sulfate, and the solvent was distilled off under about 20 mbar. 153 g of 2,4,4-trimethyl-3-(but-2-en-1-on-1-yl)-cyclohex-2-en-1-one (Ia) were obtained, the yield being quantitative, and the product being only slightly impure according to thin-layer chromatography. Recrystallization from 500 ml of cyclohexane gave 132 g (yield: 86.8% of theory) of a product which was pure according to thin-layer chromatography; evaporating down the mother liquor gave a further 21 g (yield: 13.2% of theory) of a somewhat impure product.
Reaction SMILES: C(O)(=O)C.[CH3:5][C@H:6]1[CH2:11][NH:10][C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.[C:34]([C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1)([OH:36])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:21]([N:20]([CH2:23][CH3:24])[C:18]([C:17]1[CH:25]=[CH:26][C:14]([C@H:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[N:7]2[C@@H:6]([CH3:5])[CH2:11][N:10]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[C@H:9]([CH3:12])[CH2:8]2)=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)O)cc3)C[C@@H]2C)cc1
Yield: 88.4 %

Procedure:
Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 4-carboxybenzaldehyde (1.50 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL. While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, more 4-carboxybenzaldehyde (0.75 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) was added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (10 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (5×10 mL). The aqueous solution was adjusted to pH 4.5-5 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-{(2R, 5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinyl-methyl}benzoic acid as a brittle white foam (2.34 g). The product showed a single peak on HPLC (Zorbax RX-C8, 4.6 mm×25 cm, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; λobs=210 nm, Rt=13.75 min).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=4)=[N:7][C:8]=23)=[O:15])[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 501.3 [(M+H)+]; mp 231-234° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21](I)=[C:20]([CH3:26])[CH:19]=2)[CH2:15][CH3:16])=[CH:12][CH:13]=1)=[O:8].[C:28]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[C:22]([CH3:24])=[CH:23][C:18]([O:17][CH:14]([C:11]3[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:8])=[CH:13][CH:12]=3)[CH2:15][CH3:16])=[CH:19][C:20]=2[CH3:26])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CCC(Oc1cc(C)c(I)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CCC(Oc1cc(C)c(-c2ccc(C(C)(C)C)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)s1

Procedure:
This compound is made by the general method as exemplified in Example 44 using 3-({5-[1-(4-iodo-3,5-dimethyl-phenoxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (isomer 1) and (4-tert-butyl)phenylboronic acid as the starting materials. MS (ES): 494.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:20]=[C:19]([O:21]C)[C:18]([O:23]C)=[CH:17][C:14]=1[C:15]#[N:16].B(Br)(Br)Br>C(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[CH:20]=[C:19]([OH:21])[C:18]([OH:23])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: COc1cc(C#N)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)c(O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 23 h

Procedure:
2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5-dimethoxy-benzonitrile (20.36 g, 0.0632 mol) was dissolved in warm methylene chloride (253 mL) then cooled to 0° C. Boron tribromide (1 M in CH2Cl2, 253 mL, 0.2527 mol) was added dropwise over 45 min while maintaining the temperature under 5° C., under nitrogen. The resulting mixture was allowed to warm to room temperature with stirring under nitrogen for 23 h. The resulting mixture was then cooled to 0° C. and quenched by the dropwise addition of methanol (90 mL) over 45 min. The resulting mixture was concentrated in vacuo. The resulting precipitate was suspended in methanol (2×) and concentrated in vacuo. The resulting precipitate was taken up in boiling methanol (900 mL) and hot filtered. The filtrate was concentrated to about 200 mL and allowed to crystallize. The resulting precipitate was collected via filtration to yield the title compound-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5-dihydroxy-benzonitrile—as a gray solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:7]Cl)(=O)C.[OH-].[Na+]>O>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH:6]1[CH2:5][O:4][CH2:7]1
Reactant: CC(=O)OCC(CCl)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C1CCC(OC2COC2)OC1
Yield: 100.9 %

Procedure:
To 476 g of crude 3-chloro-2-tetrahydropyranyloxy-1-propyl acetate was added 216 g (5.4 moles) of sodium hydroxide in 500 mL of water. The reaction mixture was heated at reflux for 17 hours. The upper organic layer was separated and taken up in 350 mL of methylene chloride. The methylene chloride solution was dried over sodium sulfate and solvent was removed in vacuo to leave 320.9 g of 3-tetrahydropyranyloxyoxetane: 1H NMR (CDCl3) δ1.63 (br. s, 6H, CH2); 3.2-4.4 (m, 2H, --OCH2); 4.47 (br. s, 1H, CH); 4.67 (br. s, 4H, O(CH2)); 5.17 (br, s, 1H, O--CH); IR (CH2Cl2) 2970, 2910 (C--H); 980 cm-1 (oxetane). Extraction of the aqueous layer with ether gave an additional 10.3 g for an overall crude yield of 331.2 g. 3-Tetrahydropyranyloxyoxetane distilled with some decomposition at 48°-65° (0.2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(OCC3COC(C)(C)O3)ccc2F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 320 (31 mg, 0.07 mmol) was dissolved in TFA:H2O (3:1, 10 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v:v=99.5:0.5 to 98.5:1.5) as the eluent, affording the title compound as oil. 13C NMR (CDCl3) δ 190.5, 155.4 (d), 154.6 (d), 148.9, 136.7, 134.9, 134.3, 133.3, 131.2, 130.4, 128.5, 128.2 (d), 127.1, 125.1, 120.2 (d), 117.1 (d), 115.7, 115.2 (d), 112.5, 70.3, 69.9, 63.5, 17.9
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[CH:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27])[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:8][C:7]([S:18][C@@H:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[O:27])[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(Cl)c1cccc(C(N)=O)c1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@H](C)c2cccc(C(N)=O)c2)nc2nc(N)sc12
Yield: 13 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 100 μmol) with 3-(1-chloroethyl)benzamide (20 mg, 100 μmol). Separation of the mixture by preparative HPLC gave a single diastereomer (6 mg, 13% yield) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=O)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:37]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([NH:51][NH2:52])=[O:50])=[C:47]([CH2:55][CH3:56])[C:46]=1[CH3:57])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:52][NH:51][C:49](=[O:50])[C:48]2[CH:53]=[CH:54][C:45]([O:44][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:46]([CH3:57])[C:47]=2[CH2:55][CH3:56])=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8]
Reactant: COc1cc(CC(=O)O)cc(F)c1F
Reactant: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)NNC(=O)Cc2cc(F)c(F)c(OC)c2)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
340 mg of 2-(3,4-difluoro-5-methoxyphenyl)acetic acid (B2) are dissolved in 7.0 ml of N,N-dimethylformamide under a dry argon atmosphere. 484.3 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 130.2 mg of N-hydroxybenzotriazole and 526.0 mg of 4-benzyloxy-2-ethyl-3-methylbenzohydrazide (B1) are subsequently added. The reaction solution is stirred at room temperature for 18 h overnight. When the reaction is complete (TLC check), 100 ml of water are added, and the mixture is stirred for 30 min and subsequently extracted three times with 75 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4, filtered off with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent gradient: dichloromethane/0-20% by vol. of ethanol), giving 321 mg of the title compound as a colourless oil; MS: 937.3 (2M+H+); TLC: Rf=0.50 (dichloromethane/methanol 95:5 parts by volume).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
A mixture of 4.6 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine, 1.7 g of (3R)-3-ethynyl-3-quinuclidinol, 130 mg of tetrakis(triphenylphosphine)palladium(0), 110 mg of cuprous iodide and 3.1 ml of triethylamine was stirred for 5 hours at room temperature in a nitrogen atmosphere. The reaction solution was extracted with aqueous dilute ammonia-ethyl acetate, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to NH-silica gel column chromatography using 0-5% methanol/ethyl acetate, to give 4.0 g of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[C:13]1([C:8]2[C:7]([CH3:11])=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:9]=2[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C1CCCCC1
Reactant: Cc1cc(N)n(CCN(C)C)n1
Solvent: CC(=O)O
Product: Cc1nn(CCN(C)C)c(N)c1C1=CCCCC1
Yield: 74.7 %

Procedure:
A solution of 2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazol-3-ylamine (0.998 g, 5.93 mmol) in acetic acid (10 mL) was treated with cyclohexanone (1.23 mL, 11.86 mmol) at ambient temperature for two days. The volatiles were removed and the residue partitioned between dilute sodium hydroxide and ethyl acetate. The organic phase was washed with water, concentrated and the residue purified by flash chromatography on silica gel using 10% methanol in dichloromethane to give a solid (1.10 g, 75%). MS (DCI): m/z 249 (M+H)+.