Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 1-(4-bromophenyl)ethan-1-ol (2.8 g, 13.93 mmol) and imidazole (2.84 g, 41.79 mmol) in DMF (35 mL) was added TBDMSCl (4.18 g, 27.86 mmol) at r.t., and the reaction was stirred overnight. The reaction was diluted with water (70 mL) and extracted with EtOAc (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=100:1) to give 4.08 g (95%) of the title compound as a colorless oil.
Reaction SMILES: CO[C:3]1[C:8](OC)=[C:7]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:6]=[CH:5][C:4]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1.[CH2:25]([Mg]Br)[CH3:26].[Cl-].[NH4+].O.O1CC[CH2:34][CH2:33]1>>[CH2:33]([C:8]1[C:3]([CH2:25][CH3:26])=[C:4]([C:18]2[O:19][CH2:20][C:21]([CH3:23])([CH3:24])[N:22]=2)[CH:5]=[CH:6][C:7]=1[C:11]1[O:12][CH2:13][C:14]([CH3:16])([CH3:17])[N:15]=1)[CH3:34]
Reactant: C1CCOC1
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C2=NC(C)(C)CO2)c1OC
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCc1c(C2=NC(C)(C)CO2)ccc(C2=NC(C)(C)CO2)c1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
In 20 mL of anhydrous tetrahydrofuran, was dissolved 2.00 g (6.02 mmol) of 2,2'-(2,3-dimethoxy-1,4-phenylene)-bis(4,4-dimethyl-2-oxazoline). Thereto, 16.4 mL of 0.92M ethylmagnesium bromide solution (15.1 mmol) in tetrahydrofuran was added dropwise with ice cooling in 30 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction liquid, were added successively 10 mL of aqueous saturated ammonium chloride solution and 30 mL of water. The product was extracted from the mixture with ether, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 1.98 g (100%) of 2,2'-(2,3-diethyl-1,4-phenylene)-bis(4,4-dimethyl-2-oxazoline) in a colorless prism crystal state.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH3:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Product: Cc1c(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)[nH]c2ccccc12

Procedure:
is obtained as described in Example 10 (a) from 10.0 g 4-chloro-3-sulfamoylbenzoyl chloride and 5.1 g 3-methylindole in the presence of 10.4 g aluminum chloride. Colorless crystals from isopropanol, m.p. 205° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][P:8]([CH:13](O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].C(Cl)[Cl:24].N1C=CC=CC=1>O>[CH2:5]([O:7][P:8]([CH:13]([Cl:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: ClCCl
Reactant: CCOP(=O)(OCC)C(O)c1ccc(OC)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOP(=O)(OCC)C(Cl)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
9.2 g (0.0768 mol) of thionyl chloride were added to a mixture of 20.2 g (0.0725 mol) of 4-methoxy-α-hydroxy-benzyl-phosphonic acid diethyl ester, 65 g of methylene chloride and 5.8 g (0.0725 mol) of pyridine at 20°-40° C. in the course of about 1 hour, while cooling slightly with water. The reaction mixture was then heated under reflux for 3 hours and subsequently stirred for 12 hours, without further action of heat. The mixture was poured into about 100 g of ice-water and the organic phase was separated off and dried. After distilling off the solvent, the residue was concentrated under 6 mm Hg and at 45° C. 21 g (97.7% of theory) of 4-methoxy-α-chlorobenzyl-phosphonic acid diethyl ester were obtained as a yellow viscous oil with a purity of 98.6% (gas chromatogram) and with a refractive index of nD24 : 1.5118.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N@:23]1([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH:24]1[C:26]([O:28][CH3:29])=[O:27].B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:23][C@@H:24]([CH2:25][O:14][CH2:13][C@H:12]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][OH:11])[C:26]([O:28][CH3:29])=[O:27])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of (2S,3S)-2,3-bis(benzyloxy)butane-1,4-diol (283 mg, 0.935 mmol), prepared as disclosed in Journal of Organic Chemistry 1991, 56(3), 1321-1322, and (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (110 mg, 0.468 mmol) in CH2Cl2 (1.5 mL) at −78° C. was added BF3-OEt2 (10 μL, 0.081 mmol), and the reaction mixture was stirred at −78° C. for 1 h, slowly warmed to 0° C., and then stirred at 0° C. for 3 h. The reaction mixture was directly purified by flash chromatography (SiO2) to afford the title compound as a colorless oil (208 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.45-7.20 (m, 16H), 5.70 (d, J=8.5 Hz, 1H), 4.70-4.54 (m, 6H), 4.53-4.46 (m, 1H), 3.93 (dd, J=9.5, 3.2 Hz, 1H), 3.80-3.53 (m, 9H), 2.09-1.96 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.72, 156.04, 138.16, 138.08, 136.24, 128.54, 128.49, 128.47, 128.20, 128.13, 127.99, 127.91, 127.89, 127.86, 79.03, 78.10, 73.09, 72.88, 71.40, 71.08, 67.08, 61.40, 54.46, 52.60; ESIMS m/z 538.4 ([M+H]+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1[C:52]2[C:47](=NC=CC=2)[N+:46]([O-])=N1)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:76](=O)(O)[O-:77].[Na+]>O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:46][CH2:47][CH2:52][O:77][CH3:76])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])O
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 18 h

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.036 g (0.27 mmole) of 1-hydroxybenzotriazole, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water (gradient, 20:80-100:0) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-methoxy-ethyl)-benzamide (I-28) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2sc(C)c(C(=O)CCCCl)c2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2sc(C)c(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 23.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[NH:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[Br-].[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][Zn+])[CH3:53]>C1COCC1>[CH2:52]([O:54][C:55](=[O:59])[CH2:56][CH2:57][C:13]1([OH:43])[C:12]2[CH:11]=[C:10]3[C:19]([C:20](=[O:27])[C@@:21]4([O:25][CH3:26])[C@@:8]([OH:45])([C:9]3=[O:44])[C:7]3[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=3[CH2:23][C@H:22]4[OH:24])=[C:18]([OH:28])[C:17]=2[C:16](=[NH:29])[CH:15]=[C:14]1[NH:30][C@@H:31]1[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]1)[CH3:53]
Reactant: CCOC(=O)CC[Zn+]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=N)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC1(O)C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)=CC(=N)c2c1cc1c(c2O)C(=O)[C@]2(OC)[C@H](O)Cc3cc(C)c(C(=O)OC)c(O)c3[C@]2(O)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a −78° C. solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol) in THF (2 mL) was added a solution of 3-ethoxy-3-oxopropylzinc bromide in THF (0.5 M, 1.15 mL, 0.58 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2 h, and then quenched with a saturated solution of ammonium chloride. The mixture was extracted with chloroform (3×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude was purified by preparative TLC (silica gel, 85:15 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 12-(3-ethoxy-3-oxopropyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,14-dioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (7 mg, 12%) as an orange solid and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 7.18 (s, 1H), 6.57 (s, 1H), 5.54 (s, 1H), 4.96 (s, 1H), 4.88-4.83 (m, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.75-3.66 (m, 3H), 3.57 (s, 3H), 3.34 (s, 3H), 3.25-3.16 (m, 2H), 3.03 (t, J=9.0 Hz, 1H), 2.39 (s, 3H), 2.15-1.85 (m, 4H), 1.45-1.26 (m, 1H), 1.25 (d, J=5.5 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 799 (M+H); HPLC >99% (AUC), tR 10.04 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)c1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.05 mmol of 2-isopropylbenzenethiol, and 1.05 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with ether to afford a solid (m.p. 216°-217° C.). 1H NMR (DMSO-d6) δ1.17 (d, J=6.8 Hz, 6H), 3.20 (m, 1H), 3.77 (bs, 2H), 5.64 (d, 1H), 6.45 (t, 1H), 6.92 (t, 1H), 7.12 (d, 1H), 7.32-7.48 (m, 10H).
Reaction SMILES: [CH3:1][NH:2]N.[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[NH:12])OC)=[CH:7][N:6]=1.[N:15]1C=CC=CC=1>>[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[NH:15])[NH:12][NH:2][CH3:1])=[CH:7][N:6]=1
Reactant: c1ccncc1
Reactant: COC(=N)c1ccc(Cl)nc1
Reactant: CNN
Product: CNNC(=N)c1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
Methyl hydrazine (750 mg, 16.30 mmol) was added to a solution of Methyl 6-chloronicotinimidate (1BX) (2.6 g, 15.29 mmol) in Pyridine (10 ml) at room temperature, then stirred for 1 hour. The solvent was evaporated, and residual solid triturated with cold Ether (2×10 ml) yielding title product 2BX as a yellow powder (2.4 g, 85%) MS (MH, 185)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:19]2=[C:20]3[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]2)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]3=[CH:10][C:9]=1[F:26]>CN(C)P(=O)(N(C)C)N(C)C>[N:1]1([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]4=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)CCC2C
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)c1cn2c3c(c(N4CCCCC4)c(F)cc3c1=O)CCC2C
Yield: 48.6 %

Procedure:
Anhydrous piperidine (8 g) was added to 5.3 g of 8-chloro-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine. 70 ml of hexamethylphosphoric triamide was added thereto and the mixture was allowed to react at 140° C. on an oil bath for 6 hours. After completion of the reaction any excess solvent and piperidine were removed by distillation under reduced pressure and 100 ml of ethyl acetate was added to the residue to precipitate light yellow crystals. The crystals thus obtained were separated by filtration and 300 ml of water was added thereto followed by adjusting the resulting solution to a pH of 2 with 1 N hydrochloric acid. The solution was heated and filtered. The filtrate was concentrated to 50 ml and rendered alkaline with a 10% aqueous sodium hydroxide solution to obtain 3.0 g of 8-(1-piperidyl)-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][Cl:22]>C1COCC1>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CCCCl)(C(=O)O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 2-(4-chlorophenyl)propanoic acid (13.3 g) in THF (140 mL) was added n-butyllithium (1.6M hexane solution, 90.3 mL) at −60° C. to −70° C., and the mixture was allowed to warm to −20° C. 1-Bromo-3-chloropropane (11.4 g) was added to the reaction mixture at −20° C. to 10° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.7 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)(C)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CN1CCN(Cc2nnc(-c3ccccc3)cc2-c2cccc([N+](=O)[O-])c2)CC1
Yield: 50.7 %

Procedure:
A mixture of 3-bromomethyl-4-(3-nitrophenyl)-6phenylpyridazine (0.6 g), 1-methylpiperazine (0.36 g) in isopropyl alcohol (6 ml) was refluxed for 30 minutes. After evaporating the solvent, the residue was dissolved in methylene chloride (50 ml), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3-(4-methylpiperazine-1-ylmethyl)-4-(3-nitrophenyl)-6-phenylpyridazine (0.32 g).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)[C:4]([O:6]C)=O)=O.CC(C)([O-])C.[K+].[N+:23]([NH:26][C:27]([NH2:29])=[NH:28])([O-:25])=[O:24]>C(O)C>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:3]2[C:4](=[O:6])[N:28]=[C:27]([NH:26][N+:23]([O-:25])=[O:24])[NH:29][CH:1]=2)=[CH:14][N:13]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To the solution of methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (2 g, 8.92 mmol) and potassium tert-butoxide (3.00 g, 26.8 mmol) in ethanol (15 mL) was added neat N-nitroguanidine (1.857 g, 17.84 mmol). The reaction mixture was stirred at 120° C. for 1 h. After removing the solvent, 5 mL water was added to dissolve the solid, and HCl (conc.) was used to adjust pH ˜3. The precipitate was collected to provide the title compound (1.8 g, 72.5% yield). LCMS: rt=0.96 min, [M+1-H+]=279.1
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:15](=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=O)(=O)C.Cl.[CH3:24][O:25][NH2:26].Cl>CO.C(OCC)(=O)C.O1CCCC1>[CH:18]([C:17]1[CH:16]=[C:15]2[C:7]([CH:8]([NH:26][O:25][CH3:24])[CH2:9][C:10]3([O:14]2)[CH2:13][CH2:12][CH2:11]3)=[C:6]([CH3:22])[C:5]=1[OH:4])([CH3:20])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)C)cc2c(c1C)C(=O)CC1(CCC1)O2
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CONC1CC2(CCC2)Oc2cc(C(C)C)c(O)c(C)c21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A mixture of 7-isopropyl-5-methyl-4-oxospiro[chroman-2,1′-cyclobutane]-6-yl acetate (1.0 g) and methoxyamine hydrochloride (1.0 g) in methanol (3 mL) was microwave heated at 60° C. for 3 min., 100° C. for 5 min., and 120° C. for 10 min. Two runs (total 2 g, 6.62 mmol) were combined. The solution was diluted with ethyl acetate and washed with water and brine. The crude product obtained (6.62 mmol) was dissolved in tetrahydrofuran (5 mL) and borane-pyridine complex (4 mL) at 0° C. followed by hydrogen chloride (8 mL, 4.0 M solution in dioxane) were added for 50 minutes. The solution was allowed to warm to room temperature slowly. After 48 hours, ethyl acetate was added. The solution was washed with saturated sodium bicarbonate water solution, water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 1% to 8%) gave 573 mg of 7-isopropyl-4-(methoxyamino)-5-methylspiro[chroman-2,1′-cyclobutan]-6-ol. 1H-NMR (300 MHz, CDCl3) δ=6.63 (s, 1H), 4.54 (s, 1H), 5.35 (s, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.15-3.10 (m, 1H), 2.70-2.60 (m, 2H), 2.40-2.10 (m, 6H), 2.10-1.75 (m, 3H), 1.22 (d, J=6.7 Hz, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.4, 144.9, 136.1, 123.0, 115.2,112.4, 76.7, 61.9, 52.6, 35.7, 34.4, 32.5, 27.3, 22.7, 22.6, 13.7, 11.5 ppm. MS (m/z)=245 (100, M+H+−18).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
11 g (25 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise while stirring. Stirring is continued for 2 hours at room temperature, and the mixture is washed with water, dried over magnesium sulfate and evaporated down under reduced pressure. The residue is taken up in dimethylformamide and the solution is added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of dimethylformamide. After stirring has been carried out for 2 hours at room temperature and for a further 2 hours at 60° C., the mixture is poured onto 11 of ice water and the resulting precipitate is filtered off with suction. After drying, 3.2 g of a white powder remain.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@@H:10]([OH:40])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H](O)C(=O)c1cccc(Cl)c1

Procedure:
Compound (S)-10a was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)prop-1-enyloxy)dimethylsilane (9a, 8.8 g, 0.031 mol), AD-mix-α (43.5 g), and CH3SO2NH2 (3a, 3 g, 0.032 mol) in tert-butyl alcohol-water (120 mL:120 mL). The reaction mixture was quenched with sodium sulfite (31.1 g). After purification, 4.51 g (78%) of the (S)-10a was isolated. Characterization data is similar with data reported in Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A., Tetrahedron: Asymmetry 2000, 11, 3659-3663.