Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].O.[CH3:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](=[O:13])[CH2:11][CH3:12]>CO>[CH3:6][CH2:7][CH:8]([OH:14])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12]
Reactant: CCC(=O)CC(=O)CC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(O)CC(O)CC
Yield: 90 %

Procedure:
To the mixture of 2.5 g sodium borohydride, 0.05 g sodium hydroxide, and 25 ml water, was added dropwise the solution of 14.2 g 3,5-heptandione in 30 ml methanol at 0-10° C. Upon completion, the solvent was removed by reduced pressure distillation, and the residue was continuously extracted with 40 ml ethyl acetate for 15 hours. The solvent was removed to give 3,5-heptandiol as a white solid with the yield 90%, m.p. 60-65° C. IR spectrum had a strong absorption peak at 3400 cm−1, but had no absorption peak at about 1700 cm−1.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]=1[C:18]([O:20]C)=O)=O.O>C(O)(=O)C>[CH3:12][C:9]1[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]2[C:18](=[O:20])[NH:2][N:3]=[CH:4][C:6]=2[C:10]=1[CH3:11]
Reactant: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Hydrazine hydrate (1.92 g, 38.4 mmol) was added to a solution of methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (7.96 g, 31.9 mmol) in acetic acid (38 ml) and the mixture was stirred at 90° C. for 1 hour. After this time, the reaction mixture was cooled to room temperature, poured into iced water and filtered. The crude crystals were washed with water and dissolved in a mixture of chloroform and methanol (9:1). The organic layer was separated, washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and to the residue was added a mixture of toluene and hexane. The precipitate was collected by filtration to afford the desired compound (7.02 g, 95.0%) as a pale yellowish white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)[C@@H](C)N
Reactant: CCCCCC=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCCN[C@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
D-alanine methyl ester (1.5 g, 10.75 mmol) is taken up in 50 mL methanol and is cooled to 0° C. To this is added hexanal (1.3 mL, 10.75 mmol) followed by sodium acetate (2.62 g, 32 mmol). After stirring for 15 minutes at 0° C. sodium cyanoborohydride (440 mg, 7 mmol) is added and the mixture is stirred for further 16 hours at room temperature. The methanol is evaporated and the resulting residue is taken up in ether and is transferred to a separatory funnel, washed with water (2×), dried over sodium sulfate, and is evaporated to give 1.81 g of N-hexyl-D-alanine methyl ester as a colorless oil.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C(O)C>[CH3:17][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:18])[CH2:15][OH:16]
Reactant: CC(C)(N)CO
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC(C)(CO)NC[C@H](O)c1ccc2nnnn2c1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid 6-yl)oxirane (0.25 g, 1.54 mmol) and 2-amino-2-methyl-1-propanol (0.275 g, 3.08 mmol) in 1 ml of absolute ethanol in a sealed reaction tube was heated at 120° C. (bath temperature) for two hours. The reaction mixture was concentrated under reduced pressure and then purified by preparative Tlc (silica gel; 80:20:0.5 methylene chloride:methanol: concentrated NH4OH) to afford 355 mg (92%) of product.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=[O:4].BrBr.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:5])[CH:3]=[O:4]
Reactant: C1CCNC1
Reactant: CC(C)C=O
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75 mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the solution was evaporated, stirred in DCM (8 ml) at room temperature and pyrrolidine (0.94 mL, 11.26 mmol) was added. After stirring 4 h, the mixture was diluted with brine and the layers separated. The organic layer was washed with 1M HCl and then the aqueous layer was basified with KOH to pH=10-11. This was then extracted with DCM and the organic layers were combined, dried (MgSO4), filtered and concentrated to isolate 2-methyl-2-pyrrolidin-1-yl-propanal oil as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:30][CH:31](OC)OC)[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1)=[O:8].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[CH:31]=[CH:30][N:10]2[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[C:13](=[O:23])[C:14]([OH:15])=[C:9]2[C:7]1=[O:8]
Reactant: COC(Cn1cc(C(=O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 181.5 %

Procedure:
To a solution of 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (100 mg) in dioxane (1 ml) was added conc. hydrochloric acid (1 ml) and the mixture was stirred at 90° C. for 2 hr. The solvent was evaporated, toluene was added, and the mixture was concentrated, which operations were performed twice. Crystallization from ethyl acetate-diisopropyl ether gave 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (71 mg).
Reaction SMILES: [CH2:1](/[C:8](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:16]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O.[OH-].[K+]>[CH2:1](/[C:8](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:17][C:16]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of ethyl (E)-2-benzyl-3-(2,4-dibenzyloxyphenyl)acrylate (1.5 g) and aqueous potassium hydroxide in methanol (50 mL, 15%) is stirred and heated at reflux for 3 hours. The reaction mixture is diluted with water (30 mL) plus 3 N potassium hydroxide solution (5 mL), acidified to pH 1 by addition of concentrated hydrochloric acid and the resulting solid filtered. Recrystallisation from a mixture of ethyl acetate and pentane gives E-2-benzyl-3-(2,4-dibenzyloxyphenyl)acrylic acid (1.13 g) as a white solid, m.p. 175-176° C. [Elemental analysis:- C,79.7; H,5.72%. Calculated:- C,80.0; H,5.82%].
Reaction SMILES: [NH3:1].C1COCC1.Cl[C:8]1[C:9]2[N:10]([C:14]([CH:18]3[CH2:21][CH:20]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:19]3)=[N:15][C:16]=2[I:17])[CH:11]=[CH:12][N:13]=1>C(O)(C)C>[I:17][C:16]1[N:15]=[C:14]([CH:18]2[CH2:21][CH:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:19]2)[N:10]2[CH:11]=[CH:12][N:13]=[C:8]([NH2:1])[C:9]=12
Reactant: N
Reactant: CN1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: -78 °C

Procedure:
A solution of 2N ammonia in isopropyl alcohol (350 mL) and THF (30 mL, 0.4 mol) was added to 8-chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine (19.91 g, 0.04612 mol) in a Parr bomb and cooled to −78° C. Ammonia was bubbled into the solution for 8-10 min. The bomb was sealed, stirred and heated to at 110° C. over 3 d. The solvent was then evaporated in vacuo and purified by flash silica gel chromatography (wetted with CHCl3, dried loaded with silica, and eluted with 8% (7N NH3) MeOH in CHCl3), which afforded the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.31 (1H, d, J=5.01), 7.16 (1H, d, J=6.25), 5.83 (2H, s), 3.49 (1H, m), 3.06 (1H, m), 2.76 (4H, m), 2.64 (8H, m), 2.46 (3H, s); MS (ES+): m/z 412.89/413.91 (50/10) [MH+]; HPLC: tR=0.31 min. (OpenLynx, polar—5 min.).
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=O.[BH4-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(N)c1ccccc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CNC(C)(C)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenylpropan-2-amine (1 eq.) in benzene (0.25 M) was added formaldehyde (37% w/w aqueous solution, 2 eq.). The vessel attached a Dean-Stark apparatus and heated at 80° C. for 36 h. The reaction mixture was cooled to RT, dried with Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude imine. This was then taken up in methanol (1.4 M) and added sodium borohydride (10 eq.). The resulting mixture was stirred at RT for 2 h and then quenched with 1 N aq. HCl. The volatiles were removed in vacuo and the pH of the resulting residue was carefully brought up to ˜12 with 1 N aq. NaOH. The mixture was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: COC(=O)CBr
Product: CCOC(=O)n1c(C(=O)OC)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 2) and methyl bromoacetate. 1H-NMR (CDCl3) δ: 8.08 (1H, d, J=1.8 Hz), 7.42 (1H, d, J=8.8 Hz), 7.22 (1H, dd, J=8.8, 1.8 Hz), 5.17 (2H, br s), 4.40 (2H, q, J=7.3 Hz), 3.88 (3H, s), 1.40 (3H, t, J=7.3 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C([O:14]/[CH:15]=[CH:16]/[C:17](OCC)=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CN(C=O)C>[OH:14][C:15]1[CH:16]=[CH:17][N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCO/C=C/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(O)nc12
Temperature: 110 °C

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesium carbonate (78.7 g, 242 mmol) was added and the mixture heated to 110° C. for 15 hours. The reaction mixture was cooled to ambient temperature and acidified with HOAc to pH 4. The resultant precipitate was filtered and washed with water and EtOAc, yielding the title compound as a fluffy white solid. Additional material was obtained by an aqueous workup. The filtrate was concentrated to remove the DMF, was diluted in EtOAc (500 mL) and washed with H2O. The resultant precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain additional product. The solids were pooled and dried in vacuum to afford ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (33.3 g, 100% yield) as a fluffy white solid. MS (apci) m/z=206.2 (M−H).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[Br:15][C:16]1[N:20]2[N:21]=[C:22](F)[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1.CCN(C(C)C)C(C)C>CC(O)C>[Br:15][C:16]1[N:20]2[N:21]=[C:22]([N:6]3[CH2:7][CH:2]4[CH2:8][CH:5]3[CH2:4][N:3]4[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)OC(=O)N1CC2CC1CN2c1ccc2ncc(Br)n2n1
Yield: 100.2 %

Procedure:
A solution of (1S,4S)-isopropyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.9 g, 4.2 mmol), 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.0 g, 4.6 mmol), and Hunig's base [7087-68-5] (3.0 mL, 17.2 mmol) in 2-propanol (21 mL) was stirred at reflux under N2 blanket for 3d then partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and evaporated to obtain 1.6 g of yellow solid. LRMS (ESI) m/z 380.0/382.0 [(M+H)]+, calc'd for C16H18BrN6O2: 380.24.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15]C)=[O:14])[CH:7]=[CH:6]2.O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.3 g (79 mmol) of the compound produced in part (a) above, dissolved in 200 ml of THF are slowly added to a suspension of magnesium (2.9 g, 118 Atg) in 60 ml of THF. Once the addition is complete, the mixture is heated at reflux for 2 hours at which point the temperature of the mixture is permitted to return to ambient temperature. 10.8 g (79 mmol) of anhydrous zinc chloride are added and the mixture is stirred for one hour at ambient temperature, at which point 10.5 g (39.5 mmol) of methyl 6-bromo-2-naphthoate and 500 mg of NiCl2 /DPPE complex are added. This mixture is then stirred for 2 hours at ambient temperature, poured into water, extracted with CH2Cl2, dried and evaporated. The residue is chromatographed on a silica column (eluant: mixture of heptane (70%) and ether (30%). 18.5 (90%) of the methyl ester of 6-[3-(1-adamantyl)-4 ™tert.butyldimethylsilyloxyphenyl]-2-naphthoic acid are obtained. Melting point: 152°-153° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=[O:4].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1>>[N:7]1([CH2:2][C:3](=[O:4])[CH2:5][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: O=C(CCl)CCl
Reactant: c1nc[nH]n1
Product: O=C(Cn1cncn1)Cn1cncn1

Procedure:
According to the Spanish Patent Number ES 549 020 A1 1 mole of 1,3-dichloroacetone is reacted with 2 mole of 1,2,4-triazole, then the 1,3-bis(1,2,4-triazole-1-yl)-propan-2-on obtained with low yield is reacted with 2,4-difluorophenylmagnesium bromide to give fluconazole. The yield is about 45% calculated on the Grignard reagent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[OH2:8]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][C:4](=[CH:3][C:2]([O:1][CH2:6][CH3:5])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C1CCOCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Triethyl phosphonoacetate (22.6 g, 99.88 mmol) was added to a solution of dihydro-2H-pyran-4(3H)-one (10.0 g, 99.88 mmol) in DMF (100 ml) at room temperature, and the mixture was stirred at 80° C. for 15 hr. The mixture was allowed to cool to room temperature, was diluted with water, and was extracted with ether. The organic layer was washed with water and saturated brine, was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as a yellow oil (13.2 g, yield 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:19]1[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)[C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:19]1[CH:20]=[N:21][C:22]([NH:25][C:35]3[N:36]=[CH:37][C:32]4[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:33]=4[N:34]=3)=[CH:23][CH:24]=1)[C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2COCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5COCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 75.2 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (350 mg, 1.047 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (337 mg, 1.151 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (476 mg, 0.787 mmol) in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11](OS(C)(=O)=O)[CH3:12])=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH:11]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C

Procedure:
To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:49]([CH3:51])[CH3:50])C2C=CC=CC=2N=N1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:50][N:49]([CH3:51])[C:28]([C:26]1[CH:25]=[N:24][N:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[CH:15][N:16]=3)[CH:19]=2)[CH:27]=1)=[O:30]
Reactant: O=C(O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylic acid (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (65 mg, 0.15 mmol), dimethylamine (2M in THF, 0.10 mL, 0.2 mmol) and N,N-diisopropylethylamine (0.10 mL). The mixture was stirred at RT for 2 h, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=424.1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[N:24]=[CH:23]1>>[N:30]1([C:28](=[O:29])[CH2:27][C:25]2[N:24]=[CH:23][N:22]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]4=[O:21])[CH:26]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: O=C(Cc1c[nH]cn1)N1CCOCC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(CC(=O)N4CCOCC4)c3)cc2c1=O
Yield: 39 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-(1H-imidazol-4-yl)-1-morpholin-4-yl-ethanone according to the GPB affording 18.1 mg (39%) of a yellow powder. Rt=4.37 min
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: OCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C(=O)OCc2cccnc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 50 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of 3-pyridylmethanol (0.28 g, 2.5 mmol) in dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:1) to provide 0.30 g (50% yield) of the title compound (37a) as a colorless oil. Rf=0.34 (EtOAc/Hex=1:1). 1H NMR (400 MHz, CDCl3): δ=1.01 (s, 6H), 2.24-2.31 (m, 2H), 3.20-3.25 (m, 2H), 3.64-3.67 (m, 2H), 3.81 (s, 3H), 3.85 (s, 1H), 3.94 (d, J=9.6 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.29 (d, J=10.8 Hz, 1H), 4.52 (d, J=11.2 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.31-7.34 (m, 1H), 7.71-7.73 (m, 1H), 8.60-8.66 (m, 2H) ppm. MS (ESI) m/z 500.01 (M+H)+. The analytical data was consistent with the proposed structure.