Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([N:19]=[C:20]=[S:21])[CH:14]1[O:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[I:12][C:8]1[CH:7]=[C:3]2[C:2](=[C:10]([I:11])[CH:9]=1)[NH:1][C:20](=[S:21])[N:19]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][O:18]1)[C:4]2=[O:6]
Reactant: S=C=NCC1CCCO1
Reactant: Nc1c(I)cc(I)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2cc(I)cc(I)c2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C

Procedure:
A mixture of 2-amino-3,5-diiodobenzoic acid (1.09 g, 2.57 mmol), tetrahydrofurfuryl isothiocyanate (0.35 g, 2.43 mmol) and triethylamine (0.26 g, 2.57 mmol) in 3.5 mL of ethanol was heated to reflux for about 6 h, and then was allowed to cool to room temperature. The ensuing precipitate was filtered and washed with ethanol (1×20 mL), hexanes (1×mL), and then dried to deliver 0.86 g of the title compound of Step A. 1H NMR (400 MHz, Me2SO-d6): δ 1.64-1.75 (m,1H), 1.75-1.85 (m,1H), 1.86-2.0 (m,2H), 3.57-3.65 (m,1H), 3.70-3.81 (m,1H), 4.26-4.34 (m,1H), 4.36-4.44 (m,1H), 4.52-4.60 (m,1H), 8.19 (d,1H), 8.56 (d,1H), 10.1 (br s,1H).
Reaction SMILES: O=[C:2]1[C:10]2([CH:12]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)O2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.[NH2:23][NH2:24].[CH3:25]O>C(O)(=O)C>[NH:23]1[C:2]2[C:3]3[C:8]([CH2:9][C:10]=2[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:19][CH3:25])=[O:18])=[CH:15][CH:14]=2)=[N:24]1)=[CH:7][CH:6]=[CH:5][CH:4]=3
Reactant: NN
Reactant: O=C(O)c1ccc(C2OC23Cc2ccccc2C3=O)cc1
Reactant: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(1-oxospiro[indan-2,2′-oxiran]-3′-yl)benzoic acid (750 mg), methanol (30 ml) and hydrazine hydrate (0.16 ml) was stirred at ambient temperature whilst glacial acetic acid (6 drops) were added. The mixture was boiled under reflux for 24 hours and then allowed to stand at ambient temperature for 24 hours, then cooled to 0° C. and filtered to give methyl 4-(1,4-dihydroindeno [1,2-c]pyrazol-3-yl)benzoate, m.p. 224-226° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])(C)C.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][S:22]([CH3:19])(=[O:24])=[O:23])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 17 %

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (53.2 mg, 0.19 mM) was reacted with isopropylsulfonyl chloride (2.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 2.8 mg of 379 after RP-HPLC purification (17% yield). MS (Q1) 473.2 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[NH2:21][CH2:22][C:23]1([CH3:28])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:23]([CH3:28])=[CH:22][N:21]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Reactant: CC1(CN)OCCO1
Solvent: COCCO
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2

Procedure:
500 mg of 8-methoxy-1-(phenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve®) and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrochloric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[CH:30]1([NH2:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:40][CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)=[O:28])=[CH:22][CH:23]=1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)N(CC(=O)NC1CCCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](N)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[N:17]1C=CC=CC=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](Cl)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:17][C:37]([C:32]1[C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:41])([F:40])[F:23])=[CH:26][CH:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2ccccc2nc1N
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 159.1 %

Procedure:
7-[Amino-quinoline-3-carboxylic acid ethyl ester (8.6 g, 39.8 mmol) was combined with pyridine (12.9 ml, 159 mmol) and 4-N,N-dimethylamino-pyridine (0.5 g, 4 mmol) in 100 ml of chloroform. The mixture was stirred as 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (22.64 g, 79.5 mmol) was added as a solution in 100 ml of chloroform. After heating at reflux for 2 h, the mixture was concentrated under vacuum, the residue taken up in ethyl acetate (600 ml) and washed sequentially with a 1 N aqueous hydrochloric acid solution (2×200 ml), water, and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to yield 29.4 g of a red oil. This oil was purified by chromatography on silica, eluting sequentially with a 70:30 dichloromethanelhexanes solution, followed by dichloromethane, then a 10:90 ethyl acetate/dichloromethane solution. Concentration under vacuum of the product containing fractions afforded 13.15 g of the title compound as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:26])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Yield: 92.4 %

Procedure:
1.05 g of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid prepared above was dissolved in 16 ml of acetone to prepare the solution. To the solution, 2.02 g of methyl iodide and 0.391 g of potassium carbonate were added with stirring, and then the solution was further stirred for 5 hours at room temperature. After 16 ml of water was added to the solution, the solution was extracted with two portions of 20 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation in vacuo to give 1.0 g of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (optical purity: 98% ee; yield: 92% based on the amount of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 3.0 mL (0.05 mole) of 57% ammonium hydroxide. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration (4.1 g). The crude product was recrystallized from acetonitrile/water to yield 3.9 g (87.9%) of white crystals, mp 169°-170° C.
Reaction SMILES: [C:1]1([OH:9])(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]1[CH3:7].C1(C)C(O)=CC=CC=1.[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21]>>[CH3:7][C:2]1[CH:3]=[C:4]([C:20]([OH:21])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18])[CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CC1C=CC=CC1(C)O
Agent: Cc1ccccc1O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
The procedure of Example 1 was essentially repeated, except that the xylenol was replaced with 540 g (5.0 moles) of orthocresol, and gaseous hexafluoroacetone, 83 g (0.5 mole) was added via a glass gas delivery tube reaching below the surface of the well-stirred mixture. At the completion of the reaction, as in Example 1, after recrystallization from hexane, white crystals of 1-methyl-4(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)phenol having 99.7% purity and melting at 89.5°-90.5° C. were isolated from the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][C:43]1[S:47][C:46]([CH:48]([NH2:50])[CH3:49])=[N:45][CH:44]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:50][CH:48]([C:46]2[S:47][C:43]([CH3:42])=[CH:44][N:45]=2)[CH3:49])=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1cnc(C(C)N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ncc(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (14 mg, yield 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:19])[C:17](=O)[O:16][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:18]([CH3:19])[C:17](=[S:35])[O:16][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:14]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21
Solvent: Cc1ccccc1
Product: CCC1(CC)OC(=S)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21
Yield: 36 %

Procedure:
To a stirred solution of 6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.10 g, 0.29 mmol) in toluene (5 mL) was added Lawesson's reagent (0.09 g, 0.23 mmol). The reaction mixture was heated to reflux overnight and partitioned between ammonium chloride solution (sat.) and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation using 20% ethyl acetate/hexane followed by trituration with ether gave 6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione as a white solid (0.03 g, 31%). 1H NMR (DMSO-d6): δ 8.44 (s, 1H), 7.32 (q, J=9.1 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.81 (m, 1H), 3.75 (s, 3H), 1.99 (m, 4H), 0.85 (t, J=7.3 Hz, 6H); MS (ESI) m/z 363 ([M+H]+); MS (ESI) m/z 361 ([M−H]−); Anal. calcd for C19H20F2N2OS: C, 62.96; H, 5.56; N, 7.73. Found: C, 62.15; H, 5.65 N, 7.39.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:24]C(C)([O-])C.[K+].CI>CN(C)C=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH3:24])[C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(cn1C)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In one portion, 2.0 g (5.8) mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 20 ml of dry dimethylformamide. After stirring at 0° C. for 10 minutes, 0.8 ml (12.8 mmol) of methyl iodide was added and the resulting solution was stirred for 20 minutes. The mixture was diluted with water, and the resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as orange prisms, mp 200°-202° C. A sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms, mp 203°-204° C.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH3:14][NH:15][CH3:16].O>O1CCCC1>[CH3:14][N:15]([CH2:1][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)[CH3:16]
Reactant: C=O
Reactant: CNC
Reactant: COc1ccc2[nH]ccc2c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2CN(C)C)c1
Yield: 45.1 %

Procedure:
A 37% aqueous solution of formaldehyde (11 g, 0.176 mol) was added dropwise to 10 g (0.068 mol) of 5-methoxy-1H-indole and 17 mL (0.176 mol) of 40% aqueous dimethylamine in 100 mL of tetrahydrofuran and the mixture heated to maintain reflux for 3 hours. After cooling water was added and the mixture extracted with EtOAc. The EtOAc solution was washed twice with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with a gradient, CH2Cl2→2% MeOH/CH2Cl2, to give 6.26 g (45% yield) of 1-dimethylaminomethyl-5-methoxy-1H-indole as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[SH:14])(=[O:10])[CH3:9].[CH3:39][CH:40]([CH2:42][CH2:43][CH2:44][C@H:45]([C@@H:47]1[C@:64]2([CH3:65])[C@H:50]([C@H:51]3[C@H:61]([CH2:62][CH2:63]2)[C@:59]2([CH3:60])[C:54]([CH2:55][C@@H:56]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]I)[CH2:57][CH2:58]2)=[CH:53][CH2:52]3)[CH2:49][CH2:48]1)[CH3:46])[CH3:41]>ClCCl>[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[S:14][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][O:66][C@H:56]1[CH2:57][CH2:58][C@@:59]2([CH3:60])[C:54](=[CH:53][CH2:52][C@@H:51]3[C@@H:61]2[CH2:62][CH2:63][C@@:64]2([CH3:65])[C@H:50]3[CH2:49][CH2:48][C@@H:47]2[C@H:45]([CH3:46])[CH2:44][CH2:43][CH2:42][CH:40]([CH3:41])[CH3:39])[CH2:55]1)(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Triethylamine (0.8 ml.) is added to a solution of 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranose (2.5 g.) and 6-(5-cholesten-3β-yloxy)hexyl iodide (3.3 g.) in dichloromethane (20 ml.). The solution is kept at room temperature under nitrogen overnight, and washed with water, dried, and evaporated in vacuo to a syrup (4.71 g.). This material is put on a column of silica gel and eluted with chloroform followed by 2% ethyl acetate in chloroform. The desired fractions are combined and evaporated in vacuo to give the title compound (4.0 g., 78%); Rf 0.2 (CHCl3 -EtOAc. 95:5), [α]D27 -93° C. (C 1.18, chloroform); n.m.r. (chloroform-d); δ 7.60-7.91 (4 aromatic), 1.93, 2.03, and 2.24 (3 OAc) 0.68 (CH3 -18).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][CH2:23][CH2:22]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:24][CH2:23][CH2:22]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carbaldehyde (3.0 g, 7.0 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (270 mg, 7.13 mmol) at 0° C. After being stirred at 0° C. for 15 minutes, the resulting mixture was warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with a saturated aqueous solution of ammonium chloride (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 2.85 g of the desired product as a yellow solid (yield was 95%), MS obsd. (ESI+) [(M+H)+] 430.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13][N:12]([C:22](=[O:24])[CH3:23])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCC1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (4-phenylpiperidin-4-ylmethyl) carbamic acid tert-butyl ester (2.1 mmol) in CH2Cl2 is added acetic anhydride (3.1 mmol) and triethylamine (3.1 mmol) at 0° C. The reaction mixture is stirred at room temperature for 2.5 h then the bulk of solvent is concentrated in vacuo. After the residue is suspended in AcOEt, the mixture is washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give (1-acetyl-4-phenylpiperidin-4-ylmethyl)carbamic acid tert-butyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][C:6]([CH3:13])([CH3:12])[O:7]2.[I:15](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>CO>[NH2:1][C:2]1[C:11]([I:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][C:6]([CH3:12])([CH3:13])[O:7]2
Reactant: O=I(=O)Cl
Reactant: CC1(C)CC(=O)c2c(N)cccc2O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(ccc(I)c2N)O1
Temperature: 40 °C
Yield: 43.8 %

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 6 (234 mg, 1.23 mmol), benzyltriethylammonium dichloroiodate (11, 480 mg, 1.23 mmol), sodium bicarbonate (113 mg, 1.35 mmol), CH2Cl2 (5 mL) and reagent grade methanol (2 mL). The flask was equipped with a water condenser, and the mixture was heated to 40° C. with stirring until all of compound 6 was consumed, as determined by TLC analysis. CH2Cl2 (10 mL) and 10% aqueous sodium bisulfite (10 ml) were added, the organic phase was washed with brine (1×10 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry, crude product was passed through a silica gel column using straight CH2Cl2 (Rf=0.5) as eluent. The reaction provided 171 mg (44%) of 7 as a yellow solid. 1H NMR (300 MHZ, CDCl3): δ 7.58 (d, J=9 Hz, 1H), 6.00 (d, J=9 Hz, 1H), 2.67 (s, 2H), 1.40 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 193.9, 161.3, 149.6, 145.4, 106.9, 105.8, 78.2, 73.6, 48.8, 26.5. HRMS (EI+): calculated for C11H12INO2 [M+] m/z 316.9913, found 316.9906.