Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1(O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([O:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-D-homoserine (2.53 g, 7.6 mmol) in DCM (50 ml) at 0° C. was added cyclopentanol (1.39 ml, 15.3 ml, 2 eq), EDC (1.61 g, 8.4 mmol, 1.1 eq) and DMAP (0.093 g, 0.76 mmol, 0.1 eq). The reaction mixture was stirred for 16 hours at room temperature before evaporation under reduced pressure. The crude residue was dissolved in ethyl acetate (100 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 2.24 g, 73% yield of title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([CH2:16][OH:17])[O:11][C@H:10]1[N:18]1[C:30]2[C:29]3[NH:31][C:32]4[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=4[C:28]=3[C:27]3[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=3[C:25]=2[C:24]2[C:19]1=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:47](Cl)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:47]([O:17][CH2:16][C@H:12]1[O:11][C@@H:10]([N:18]2[C:30]3[C:29]4[NH:31][C:32]5[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=5[C:28]=4[C:27]4[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=4[C:25]=3[C:24]3[C:19]2=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=3)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]([OH:15])[CH2:13]1)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](O)[C@H]1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H](O)[C@@H](OCc2ccccc2)[C@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 12-[4-deoxy-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.500 g, 0.79 mmol) in 6 mL of dry DMF, at 5° C. under Ar, was added tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol). After stirring this mixture at room temperature for 20 h it was re-cooled at 5° C. and more tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol) were added. The resulting mixture was stirred at room temperature for 2.5 h and then it was diluted with ethyl acetate, washed (1M NaHCO3, brine), dried (MgSO4) and evaporated. Chromatography (SiO2/20-35% ethyl acetate-hexane) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (0.474 g, 69%); MS (ESI−) m/e 870 (M−H)−. To a solution of a portion (0.050 g, 0.057 mmol) of this material in 2 mL of dichloromethane was added a suspension of Dess-Martin periodinane (0.048 g, 0.114 mmol) in 3 mL of dichloromethane and the mixture was stirred for 30 min. The mixture was then diluted with ethyl acetate, washed (cold 30% aq. Na2S2O3,1M NaHCO3, H2O, brine), dried (MgSO4) and evaporated. Prep tlc (SiO2/ethyl acetate-hexane, 2:3) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-oxo-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.035 g, 70%) as a gum which solidified on standing; MS (ESI−) m/e 868 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([F:17])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Br)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Cl)cc(Br)c1F
Yield: 117.9 %

Procedure:
A solution of tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (900 mg, 2.78 mmol) in DCM/TFA (1:1, 20 mL) was stirred at rt for 1 h. The reaction mixture was concentrated, then the residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound (736 mg). MS m/z 223.9 (M+1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)C.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(#N)C>[N:7]1([CH2:6][CH2:5][CH2:4][NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(CCn1ccnc1)OCC
Reactant: CC(C)(N)CO
Solvent: CC#N
Product: CC(C)(CO)NCCCn1ccnc1

Procedure:
3-(Imidazol-1-yl)propionaldehyde diethyl acetal (8.1 g) was converted into the free aldehyde, as described in Example 24, and then added to a mixture of 2-amino-2-methylpropanol (1.83 g) in acetonitrile (40 ml) and 4A molecular sieves (6.0 g). The mixture was reacted following the procedure of Example 24 to give 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol, m.p. 81-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH3:39])[C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:35]([CH3:39])[C:36]([NH2:38])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C(N)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.00 g) and 2-bromopropanamide (0.70 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.50 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.03 g, 88%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 111 %

Procedure:
13.27 g (37.2 mmol, 95% pure) of tert-butyl(+/−)-{4-[(acetyloxy)methyl]phenyl}(cyclopentyl)acetate were dissolved in 117 ml of dichloromethane, the mixture was cooled to 0° C. and 58.4 ml of trifluoroacetic acid were added. The reaction mixture was initially stirred at 0° C. for 1.5 h and then at RT for a further 1.5 h. The mixture was then concentrated under reduced pressure and the residue was dried under high vacuum. The residue was taken up in 50 ml of dichloromethane, and the solution was washed four times with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Drying under high vacuum gave 11.41 g of the title compound which were used without further purification for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][OH:19])=[O:12])[S:10][C:3]=12.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[O:12])[S:10][C:3]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 16 h
Yield: 126.5 %

Procedure:
To a stirred solution of 7-chloro-2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 3a (4.50 g, 15 mmole) were added t-butyldimethylchlorosilane (3.18 g, 21 mmole) and triethylamine (3.4 ml, 2.47 g, 24 mmole). The resultant reaction mixture was stirred at ambient temperaure for 16 hours. The crude reaction mixture was poured into water (150 ml) and extracted with CH2Cl2 (150 ml). The combined organic extracts were washed with brine (150 ml), dried over Na2SO4 and concentrated, in vacuo, to give 7.8 g of an orange syrup, which was purified by silica gel chromatography. Elution with Et2O:hexane (67:33) and evaporation of the appropriate fractions gave 5.73 g (92%) of an off-white solid. 1H NMR (DMSO-d6): δ8.72 (1H, d, J=5.0 Hz), 8.07 (1H, s), 7.68 (1 H, d, J=5.0 Hz), 4.30-4.15 (1H, m), 3.94-3.67 (4H, m), 2.12-1.81 (4H, m), 0.85 (9H, s), 0.03 (3H, s), 0.00 (3H, s). Anal. Calcd. for C19H27N2O2SClSi: C, 55.52; H, 6.62; N, 6.82; S, 7.80; Cl, 8.63. Found: C, 55.49; H, 6.46; N, 6.92; S, 7.80; Cl, 8.88.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH2:26](Cl)Cl>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:26][CH:12]3[N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(/C=C/c2ccc3c(c2)COC3=O)CC1
Reactant: ClCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCN(C2CC2c2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-[(E)-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethenyl]piperazine-1-carboxylate (1.1 g, 3 mmol) in 30 mL of DCM was added Pd(OAc)2 (100 mg) and was cooled by ice/water. 50 mL of newly prepared CH2N2 solution was added dropwise. The reaction was warmed to room temperature and stirred over night. The solid was filtered off, and the filtrate was evaporated at reduced pressure to get crude product, which was purified via prep-HPLC to afford tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)cyclopropyl]piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CC(C)=O.O>[C:25]([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:36](=[O:37])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:27])[NH2:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: NC(=O)OC(CCN1CCN(c2ccc(OC(=O)OCc3ccccc3)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (1 mmol) prepared in Example 88 was dissolved in acetone (20 mL), and triethylamine (2 mmol) was added and benzyl chloroformate (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: C(N)C1C=CC=CC=1.C(=O)(O[CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC1(C)C(C=CC2CCC/C(=C/C=C3/C(C)(C)C4C(N/3CCCCS(O)(=O)=O)=CC=CC=4)/C=2OC2C=CC(OCCCCNCC3OC(O)C(N)C(O)C3O)=CC=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2.C(Cl)(Cl)Cl>[C:16]1([CH:15]([C:24]2([NH2:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH2:25]2)[CH:14]=[CH2:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)OCC=Cc1ccccc1
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: NCc1ccccc1
Product: C=CC(c1ccccc1)C1(N)C=CC=CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
By the procedure for reaction of benzylamine with methyl cinnamyl carbonate, the reaction of aniline (130 mg, 1.40 mmol) and methyl cinnamyl carbonate (188 mg, 0.980 mmol) with [(COD)Ir(κ2-L1)L1] (Ir-2) (13.8 mg, 0.0100 mmol) and [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) as catalyst was conducted at room temperature for 2 h. 1H NMR analysis of the crude reaction mixture indicated that the ratio of regioisomers was greater than 99/1. The mixture was then purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give 81% yield. HPLC analysis indicated that the enantiomeric excess of the product was 97% [Diacel Chiralcel® OD-H (0.46 cm×25 cm); hexanes/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=19.1 (major) min., 20.3 min. (minor)]. [α]D20=−12.0 (c 2.10, CHCl3); 1H NMR (400.13 MHz, C6D6) δ 7.44-7.24 (m, 5H), 7.20-7.10 (m, 2H), 6.69 (t, J=7.2 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 6.04 (ddd, J=16.8, 10.4, 6.4 Hz, 1H), 5.28 (dt, J=17.2, 1.2 Hz, 1H), 5.22 (dt, J=10.0, 1.2 Hz, 1H), 4.94 (t, J=4.4 Hz, 1H), 4.04 (br s, 1H). 13C NMR (100.5 MHz, C6D6) δ .61.1 (s, CH), 114.2 (s, CH═CH2), 115.9 (s, CH═CH2), 118.2, 127.7, 127.8, 129.1, 129.6, 139.6 (all s, Ar—CH), 142.4 (s, Ar—C), 147.8 (s, Ar—C).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[S:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C1C=CC=CC=1>[CH3:12][C:9]([C:7]1[CH:6]=[C:5]([I:13])[C:4]2[O:14][C:18]3([CH2:19][CH2:20][S:15][CH2:16][CH2:17]3)[NH:1][CH2:2][C:3]=2[CH:8]=1)([CH3:11])[CH3:10]
Reactant: O=C1CCSCC1
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(I)c2c(c1)CNC1(CCSCC1)O2
Yield: 62 %

Procedure:
A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (3.0 g., 0.01 mole), tetrahydrothiopyran-4-one (1.18 g., 0.01 mole), and benzene (100 ml.), is refluxed under a Dean-Stark trap for 4 hr. The solvent is evaporated, and the residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro-[2H-1,3-benzoxazine-2,4'-tetrahydrothiopyran], (2.5 g.), m.p. 123°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].S(=O)(=O)(O)O.C(O)(=O)C.[N:32]([O-])=O.[Na+]>O1CCCC1.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=[CH:12][C:2]=2[N:1]=[N:32]1
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2nnn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate (0.89 g), concentrated sulfuric acid (1.0 g) were stirred in a mixed solvent of acetic acid (20 ml), water (10 ml) and tetrahydrofuran (20 ml). Sodium nitrite (3.0 g) was added thereto, and the mixture was stirred at room temperature for 30 min. The solvent was distilled away, and water was added to separate the toluene layer. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The toluene layer was concentrated to give the objective compound (0.64 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>ClCCl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)Oc1ccc(O)cc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-tert-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad12/25, flash 12, dichloromethane) followed by a recrystallization from ethanol (41%, crystals). HPLC-MS m/z=300.3 (M+1), Rt: 4.7 min.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.S([O-])(O[CH2:17][CH2:18]CCCCCCCCCC)(=O)=O.[Na+].O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1.C([Mg]Br)C=C>O.C(OCC)C>[C:7]1([C:2]([OH:6])([CH2:1][CH:17]=[CH2:18])[CH3:32])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(c2ccccc2)OCCO1
Agent: C=CC[Mg]Br
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=CCC(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 343.4 %

Procedure:
2-Methyl-2-phenyl-1,3-dioxolane (0.5 g, 3 mmol), sodium dodecyl sulfate (0.2 g, 0.7 mmol) and a stir bar were added to the inside of a PDMS thimble. p-Toluene sulfonic acid monohydrate (0.145 g, 0.8 mmol) dissolved in 4 mL water was added to the inside of the PDMS thimble followed by 2 mL of hexanes. The reaction was stirred at 25° C. for 5 hours. Hexanes (5 mL) and 24 mL of 1 M allyl magnesiumbromide (3.49 g, 24 mmol) in diethyl ether was added to the outside of the PDMS thimble and the reaction was stirred for 14 hours. Water (5 mL) was added. The PDMS thimble was swelled with 20 mL hexanes and 2×20 mL diethyl ether and the organics were combined and dried over MgSO4. The product was purified by flash chromatography eluting with 100% hexanes initially, increasing to 1:49 ethyl acetate:hexanes to yield a colorless oil (0.39 g, 79% yield). 1H NMR (CDCl3): δ 1.54 (s, 3H), 2.09 (s, 1H), 2.49 (dd, J=13.8, 8.4 Hz, 1H), 2.68 (dd, J=13.5, 6.3 Hz, 1H), 5.09-5.16 (m, 2H), 5.55-5.66 (m, 1H), 7.21-7.26 (m, 1H), 7.31-7.36 (m, 2H), 7.41-7.45 (m, 2H). 13C NMR (CDCl3): δ 29.86, 48.42, 73.58, 119.43, 124.72, 126.57, 128.13, 133.63, 147.59.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.C[N:17]([CH:19]=O)C.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:27][CH:26]=1)=O>O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([N:7]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:27][CH:26]=4)[N:17]=[C:19]3[CH2:22][CH2:23][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: O
Product: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CCc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5.2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was extracted in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2–4% MeOH/DCM (yield ˜22%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:16][CH2:17][NH:18][CH2:19][C:11]3=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:8]=1.C([N:28](CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:28][CH:19]1[C:11]2=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]3[CH:8]=[C:7]([Cl:6])[CH:15]=[CH:14][C:13]=3[N:12]2[CH2:16][CH2:17][NH:18]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)c1n2CCNC1
Solvent: ClCCl
Product: O=C(CCl)NC1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Temperature: 39 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
A solution of chloracetyl chloride (4.60 g, 0.0407 mole) in dichloromethane (25 ml) is added over a period of three-fourth hours to a solution of 8chloro-10-phenyl-1,2,3,4-tetrahydropyrazino[1,2-a] indole (10.0 g, 0.0353 mole) and triethylamine (4.13 g, 0.0407 mole) in dichloromethane (100 ml). An exotherm raises the temperature to 39° C. The reaction mixture is stirred at room temperature for 6 hours, then allowed to stand overnight. It is concentrated to dryness. The residue was taken up in dichloromethane (500 ml), washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the filtrate is concentrated to dryness. The residue is recrystallized twice from isopropanol, giving the above titled product, 6.94 g (54.7% yield), melting at 139°-149° C.