Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:4].Cl[CH2:14][C@@H:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.CC(C)([O-])C.[Na+].N#N>CN(C=O)C>[CH3:20][C:17]1([CH3:21])[O:16][C@H:15]([CH2:14][N:8]2[CH:9]=[CH:10][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:12])([CH3:11])[CH3:1])=[N:7]2)[CH2:19][O:18]1
Reactant: CC(C)(C)C(=O)Nc1cc[nH]n1
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(C)(C)C)n2)O1
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (1.67 g, 10 mmol) was dissolved in DMF (17 ml). (S)-4-Chloromethyl-2,2-dimethyl-[1,3]dioxolane (1.52 g, 10 mmol) was added into the mixture. Finally Sodium tert-butoxide (0.98 g, 10 mmol) was added at room temperature. The mixture was heated to 100° C. with agitation for 23 hours under N2 atmosphere. UPLC indicated that there was 26% 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide remained in the mixture. Additional 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (0.76 g, 5 mmol) and Sodium tert-butoxide (0.49 g, 5 mmol) was added. The mixture was stirred at 100° C. for another 24 hrs. HPLC indicated 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide was 9.4% remained, the selectivity of N1/N2 alkylation products was 2.8:1. The DMF was concentrated under reduced pressure. Water (10 ml) was added. The mixture was extracted with DCM (2×12 ml), the organic layer was washed with 10% aqueous NaCl (2×20 ml). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (0.84 g), yield: 30%. 1H-NMR (400 MHz, d6-DMSO): δ 9.85 (s, 1H), 7.59 (s, 1H), 6.47 (s, 1H), 4.36-4.39 (m, 1H), 4.08-4.12 (m, 2H), 4.0-4.02 (m, 1H), 3.73-3.75 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.19 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:19]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C1COCCOCCOCCOCCOCCN1
Product: CC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and pivalyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:22]=[CH:21][C:17](C(O)=O)=[CH:16][CH:15]=1)=[O:13].C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:21]=[CH:22][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
1 g (4.45 mmol) of 1-bromo-4-(trifluoromethyl)benzene and 0.73 g (4.9 mmol) of 4-formylbenzoic acid are added to 30 ml of dimethoxyethane and mixed with 15 ml of 1M sodium carbonate solution. 110 mg of tetrakis (triphenylphosphine)palladium(II) are added, and the mixture is then heated at reflux temperature for 18 hours. The reaction solution is cooled, dichloromethane and water are added, the mixture is filtered through Extrelut and the solvent is distilled off under reduced pressure.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=O)C.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=[O:3])[NH2:13]
Reactant: CCOC(=O)CC[Sn](C)(C)C
Reactant: NN
Solvent: CCO
Product: C[Sn](C)(C)CCC(=O)NN
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 8 g (30 mmoles) of 2-(ethoxycarbonyl)ethyltrimethylstannane (compound 47), 5 ml of 95% hydrazine (150 mmoles) in 10 ml of ethanol was refuxed for 2 hours. The volatiles were removed at reduced pressure. Distillation of the crude product afforded 5.26 g of 2-(hydrazinocarbonyl)ethyltrimethylstannane, b.p. 92°-98° C. (0.07 mm), compound 42 of Table I. The infrared spectrum of the distillate showed the following characteristic absorptions: 3300 cm-1 (N-H), 1660 cm-1 and 1530 cm-1 ##STR21## and 760 cm-1 (--Sn(CH3)3). A gas chromatogram of the sample showed a single peak on a 6 feet × 1/8 inch commercially obtained column packed with 10% of silicone gum rubber on silanized diatomaceous earth. The NMR spectrum exhibited the following proton absorptions: a broad singlet at 752 Hz (1 proton) assigned to N-H, a singlet at 388 Hz (2 protons) assigned to NH2, a triplet centered at 235 Hz (2 protons) assigned to ##STR22## a triplet centered at 98 Hz (2 protons) assigned to CH2 -Sn, and a singlet centered at 6 Hz (9 protons) assigned to Sn(CH3)3.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:9])[CH3:8]>N1C=CC=CC=1>[C:7]([O:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]2[CH3:27])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCCC(=O)Cl
Reactant: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Solvent: c1ccncc1
Product: CCCC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reaction time: 18 h

Procedure:
Butyryl chloride (185 μl) was added dropwise to a solution of 6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (50 mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4 ml). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>7/3 (v/v) as eluent.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)Cc1ccc(F)cc1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCOC(=O)N=C(Cc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0° C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes. The solids were removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (3×10 mL). The combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-(4-fluorophenyl)acetimidate (0.99 g, 52.7%) as an amorphous yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, J=8.5, 5.6 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.15 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][C@@:8]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:31])[C@@:25]5([O:30]C(=O)CC5)[CH2:24][CH2:23][C@H:22]4[C@@H:17]3[CH:16]=[CH:15][C:14]1=[CH:13][C:11](=[O:12])[CH2:10][CH2:9]2.C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:9]1[C@@:8]2([CH3:7])[C:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C:25]2=[O:30])=[CH:13][C:11](=[O:12])[CH2:10]1
Reactant: C=CCCCBr
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@]12C(=CC(=O)C[C@@H]1CCCCCBr)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 7 %

Procedure:
Cp2ZrHCl (206 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 5-bromo-1-pentene (0.12 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 15 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (30.0 mg, 0.040 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before Canrenone (136.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (30:70 EtOAc/petrol; SiO2) gave major diastereomer (4) (+)-7α-(5-bromopentyl)-17α-hydroxy-3-oxo-pregn-4-ene-21-carboxylic acid γ-lactone (64 mg, 0.13 mmol, 33%) and minor diastereomer (4a) (+)-1α-(5-bromopentyl)-4-androstene-3,17-dione (14 mg, 0.028 mmol, 7%). Diastereomeric ratio was determined by integration of 1H NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:28][CH3:29])[C:6](=[O:15])[N:5]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC(F)(F)F
Reactant: CCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(Cl)nc2n(CC(F)(F)F)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione (0.070 g, 0.23 mmol) in anhydrous DMF (2 ml) was added caesium carbonate (0.085 g, 0.26 mmol) followed by 1-iodoethane (0.061 g, 0.39 mmol). The mixture was heated for 5 h at 80° C. then stirred for 16 h at ambient temperature under an atmosphere of nitrogen. The solvent was removed under reduced pressure using a vacuum centrifuge and the residue dissolved in anhydrous THF (2.5 ml). To the mixture was added palladium tetrakis (0.030 g, 0.026 mmol) and morpholine (0.040 g, 0.45 mmol) and the reaction mixture degassed using nitrogen then stirred at ambient temperature for 72 h. The mixture was partitioned between chloroform and 2N HCl aq., and the aqueous layer re-extracted. Organic extracts were combined and evaporated under a stream of nitrogen then purified using aminopropyl SPE (eluting with acetic acid:methanol:DCM, 1:2:2) to give the title compound as a white solid in >95% purity (0.041 g, 60%). NMR δH (400 MHz, d4-MeOD) 1.20 (t, 3H, J=7 Hz), 4.03 (q, 2H, J=7 Hz), 4.73 (q, 2H, J=8.5 Hz), m/z 297 [MH+].
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH:21](C)C)[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1C=C2C(=CC=1)N(CCC)[C:31](=[O:39])C2=O.COC1C=CC(C)=NC=1>>[OH:25][C:9]1([CH2:8][C:3]2[CH:2]=[CH:7][C:6]([O:39][CH3:31])=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]1=[O:24]
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Agent: COc1ccc(C)nc1
Product: CCCN1C(=O)C(O)(Cc2ccc(OC)cn2)c2cc(C)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-methyl-1-propylindoline-2,3-dione and 5-methoxy-2-methylpyridine. 1H-NMR δ 8.3 (s, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 6.98 (d, 1H), 6.73 (m, 2H), 4.2 (bs, OH), 3.92 (s, 3H), 3.61 (m, 2H), 3.23 (d, 1H), 3.12 (d, 1H), 2.62 (s, 3H), 1.70 (m, 2H), 0.97 (t, 3H). Calculated mass for C19H22N2O3, 326.16. Observed, 327.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[N:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]#[N:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1cnc2cc(N3CCNCC3=O)ccc2c1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4cc(C#N)cnc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 7-(2-oxopiperazin-1-yl)quinoline-3-carbonitrile [I-9] (20 mg, 0.079 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (30 mg, 0.16 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 2 hours. LC showed formation of the title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 443 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[C:9]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:8]2[C:9]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:10][CH:11]=[CH:12][CH:13]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)c1cccnc1-n1ccnc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 4.8 g of 3-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine in 35 ml of ethanol and 5 ml of water is added 0.64 g of sodium borohydride. After the mixture is stirred at room temperature for an hour, the reaction mixture is poured into water and extracted with chloroform. The chloroform is distilled off and the residue is recrystallized from toluene to give 4.3 g of α-(4-chlorophenyl)-2-(1-imidazolyl)-3-pyridinemethanol as white crystals, melting at 133°-134° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH2:40][C@H:41]([OH:44])[CH2:42][OH:43].OCC[C@H]1COC(C)(C)O1>>[OH:44][C@H:41]([CH2:42][OH:43])[CH2:40][CH2:39][NH:38][C:32]([N:12]1[C@@:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C@@:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: NCC[C@H](O)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: CC1(C)OC[C@H](CCO)O1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NCC[C@H](O)CO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-4-amino-butane-1,2-diol (prepared from (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H41C12N4O4 [(M+H)+] 627.25, observed 627.2497.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11]C)=[O:10])[CH2:2]2.[C:13](=[N:17][OH:18])([NH2:16])[CH2:14][CH3:15].[H-].[Na+].CC(O)C.ClCCl.[CH3:28][OH:29]>O1CCCC1>[C:9]([OH:11])(=[O:10])[C:28]([OH:18])=[O:29].[CH2:14]([C:13]1[N:17]=[C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[O:11][N:16]=1)[CH3:15]
Reactant: CO
Reactant: CCC(N)=NO
Reactant: COC(=O)C1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)O
Product: CCc1noc(C2CN3CCC2CC3)n1
Product: O=C(O)C(=O)O

Procedure:
The title compound free base (17 g, 77%) was prepared from methyl quinuclidine-3-carboxylate (18.0 g, 0.11 mol), propionamide oxime (14 g, 0.16 mol) and sodium hydride (7 g of a 55% oil dispersion, 0.16 mol) in anhydrous tetrahydrofuran (350 mL). The hydrogen oxalate salt had mp 113°-115° C. (propan-2-ol). Rf 0.3 in dichloromethane/methanol (50:1) on alumina plates. (Found: C, 52.25; H, 6.41; N, 14.07. C11H17N3O.C2H2O4 requires C, 52.52; H, 6.44; N, 14.13%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1
Yield: 95.1 %

Procedure:
Tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (4.08 gm) was reacted with 2.79 g 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to yield 4.38 g tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate. 150 mg of this crude intermediate was subjected to General Procedure D and subsequently reacted with 84 mg D-lactic Acid via General Procedure B to give 28 mg of 398 after reverse phase HPLC purification. MS (Q1) 485.3 (M)+.
Reaction SMILES: [H-].[Na+].CCCCCC.C(OP([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH:22]=1)(OCC)=O)C.[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]>CN(C)C=O>[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23][C:21]2[CH:22]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]
Reactant: CCOP(=O)(OCC)c1cccc(CCCC(C)=O)c1
Reactant: CCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCc1cccc(C=CC(=O)CCCc2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
49 mg (1.13 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice, each time with hexane, and were suspended in 6 ml of dimethylformamide. 2 ml of a dimethylformamide solution containing 289 mg (0.97 mmol) of 5-diethoxyphosphoryl-1-(4-oxopentyl)benzene were added to the suspension, whilst ice-cooling. The reaction mixture was then immediately allowed to return to room temperature, after which it was stirred for 30 minutes. 300 mg (0.808 mmol) of N-(2-ethyl-6-formylphenyl)-2-(9H-xanthen-9-yl)acetamide were then added to the reaction mixture, once again whilst ice-cooling. The mixture was then stirred for 1 hour at the ice-cooling temperature and then for 3 hours at room temperature. At the end of this time, the reaction solution was poured into ice-water and extracted with diethyl ether. The organic extract was washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 220 mg (yield 53%) of the title compound as crystals, melting at 168°-170° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:31][C@H:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:5][C:6]([F:30])=[C:7]([S:9]([N:12](CC2C=CC(OC)=CC=2OC)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:4]([O:31][C@H:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:5][C:6]([F:30])=[C:7]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C#N)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 89.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-cyano-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (32.3 mg, 0.0545 mmol) prepared in Example 62d, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (21.5 mg, 89%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.C(Cl)(=O)OCC.[NH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:23][CH:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:16])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: NC1CN2CCC1CC2
Reactant: CC1Oc2c(cc(Cl)cc2C(=O)O)NC1=O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1Oc2c(cc(Cl)cc2C(=O)NC2CN3CCC2CC3)NC1=O
Product: Cl

Procedure:
A solution of 4.8 g of 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 100 ml of tetrahydrofuran is cooled to below 0° C. and 5 ml of triethylamine is added under stirring thereto. Further, 2.5 g of ethyl chlorocarbonate is added and the mixture is stirred at room temperature for an hour. To the resultant mixture is added 3.0 g of 3-aminoquinuclidine and the mixture stirred for 4 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is converted into the corresponding hydrochloride by treating with ethanolic hydrochloric acid followed by recrystallizing from ethanol-water to give 6-chloro-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 325°-328° C. with decomposition.