Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br-].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=O>O1CCCC1.BrCCBr>[Br:24][C:20]1[CH:19]=[C:18]([C:16]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=2)=[CH2:15])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: Cc1cc(Br)ccc1OC(C)C
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1cccc(Br)c1)c1ccc(OC(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of magnesium turnings (811 mg, 33.38 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 4-bromo-1-isopropoxy-2-methyl-benzene (7.0 g, 30.6 mmol, 1.1 eq in 25 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (5.54 g, 27.81 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LC-MS showed complete conversion to the desired product. 50 mL of water were added followed by 35 mL of 1 M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 mL of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was poured in the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, aq. NaHCO3 and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 6.8 g of clean product was obtained as colorless liquid (yield: 66%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)[CH2:7]2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:43].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O.C(N(CC)CC)C>[ClH:43].[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:40]3[CH2:41][CH2:42][CH:37]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:38][CH2:39]3)=[O:28])=[CH:24][CH:23]=1)[CH2:5]2
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)O)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)N3CCC(N4CCCCC4)CC3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
The mixture of 4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzoic acid (2.00 g), 4-piperidinopiperidine (1.62 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.84 g), 1-hydroxybenzotriazole monohydrate (1.47 g), and triethylamine (2.01 ml) in THF (40 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=1:2) and converted into its hydrochloride, which was further recrystallized from ethanol-diisopropylether to yield the entitled compound (2.85 g) as crystals.
Reaction SMILES: C([O:5]O)(C)(C)C.C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:19][C:16]=1[CH:17]=[CH2:18].O>C(Cl)Cl.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.O=[V]>[Cl:14][C:15]12[O:5][C:16]1([CH:19]=[C:20]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:21]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:22]2)[CH:17]=[CH2:18]
Reactant: CC(C)(C)OO
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)cc1Cl
Agent: O=[V]
Agent: CC(=O)/C=C(/C)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=CC1(Cl)O2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
19 g of vanadylacetylacetonate in solution of 50 ml of methylene chloride were cooled to 0° C. and 3.5 ml of terbutyl hydroperoxide in a toluene solution (3M/l) were added over 30 minutes. The mixture was stirred for 20 minutes at 0° C. and 2.63 g of the product of Stage D in solution in 10 ml of methylene chloride were added. The reaction mixture was stirred for 3 hours at ambient temperature and 30 ml of water were added. The organic phase was separated and the solvent was eliminated under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride-acetone 8-2) to obtain 21.8 g of the expected product with a Rf=0.35 (CH2Cl2 -acetone 8-2).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14](=[O:30])[CH2:15]P(OCC(F)(F)F)(OCC(F)(F)F)=O)[CH3:12].C1OCCOCCOCCOCCOCCOC1.[C:49]1([CH3:57])[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=O)[CH:50]=1>C1COCC1>[CH2:11]([O:13][C:14](=[O:30])[CH:15]=[CH:57][C:49]1[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=1)[CH3:12]
Reactant: CCOC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: Cc1cccc(C=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(C)c1
Reaction time: 0.5 h

Procedure:
KHMDS (4.0 g, 20.0 mmol) was added to a solution of ethyl[bis(2,2,2-trifluoro-ethoxy)phosphinyl]acetate (4.7 mL, 20.0 mmol) and 18-crown-6 (10.6 g, 40.0 mmol) in THF (200 mL) at −78° C., and stirred for 30 minutes. m-Tolualdehyde (2.1 mL, 18 mmol) was added and the reaction mixture was stirred for 3 hours from −78° C. to room temperature. The reaction was quenched with aqueous hydrochloric acid (1 M solution, 100 mL), and the product was extracted with EtOAc (3×100 mL). The organic extracts were washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C12H14O2+H: 191, observed: 191.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:18]=[C:4]2[N:3]=1.O.C1COCC1.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[N:18]=[C:4]2[N:3]=1
Reactant: Fc1ccc(-c2c(Cl)nc3nc(C4CC4)nn3c2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2cn3nc(C4CC4)nc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
7.78 g (24.1 mmol) 5,7-Dichloro-2-cyclopropyl-6-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine are given in 612 mL ethanol, 435 mL water and 234 mL THF. After addition of 6.1 g (114 mmol) NH4Cl, 10.1 g (154 mmol) zinc powder are added and the mixture is stirred at room temperature for 3 h. Stirring is continued over night. The reaction mixture is filtered via a glass microfibre filter and the filter is washed with plenty of methanol. The zinc slurry is stirred twice with ethylacetate/methanol (250 mL each) and the combined organic filtrates are evaporated. The residue is extracted with ethyl acetate (1 L). The organic phase is washed twice with brine and dried over Na2SO4. After evaporation of the solvent, the residue is purified by chromatography on silicagel (eluents dichloromethane/methanol) yielding 0.76 g (10.4%) of the desired product. Additionally 3.57 g are obtained which are a mixture of the desired product and the bis deschloro derivate (ratio 6:4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccncc6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.08 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=C)[C:5]=2[N:6]=[CH:7][N:8]=1.[O:14]=[O+][O-].N#N.CSC>C(Cl)(Cl)Cl.CO>[CH3:1][S:2][C:3]1[C:4]2[S:11][CH:10]=[C:9]([CH:12]=[O:14])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C=Cc1csc2c(SC)ncnc12
Reactant: O=[O+][O-]
Agent: N#N
Solvent: CSC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1ncnc2c(C=O)csc12
Temperature: 25 °C

Procedure:
4-(Methylthio)-7-vinylthieno[3,2-d]pyrimidine (350 mg, 1.68 mmol) was dissolved in CHCl3/MeOH (2 mL/2 mL) and treated with ozone at 78° C. for 30 minutes. When the starting material was disappeared, the reaction mixture was treated with N2 gas at the same temperature for 5 minutes, heated to room temperature, and dimethylsulfide (0.37 mL, 5.04 mmol) was added thereto. The reaction mixture was concentrated to obtain a yellow solid. The solid was filtered, washed with diethyl ether and dried with N2 gas to obtain the title compound without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:5](=[O:7])[C:4]1[C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(F)cc1C(=O)O
Product: CCN1CCCC1CNC(=O)c1cc(F)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 84 %

Procedure:
In a manner identical to Example 15, 3-fluoro-6-geranyloxybenzoic acid(1.46 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.68 g(84%) of the aimed compound.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH2:20][O:19][C@H:18]([CH2:21][O:22]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@@H:8]1[O:9]C(=O)C)[OH:7])(=O)C.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:20]1[O:19][C@H:18]([CH2:21][OH:22])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@:6]1([OH:7])[CH2:5][OH:4]
Reactant: CC(=O)OC[C@H]1OC[C@@](O)(COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OC[C@H]1OC[C@@](O)(CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol 17 (2.8 kg, 7.73 mol) was added to chloroform (14 lit.) in 25 lit. round bottom flask with mechanical stirring. The reaction mixture was cooled to 0° C., and 0.5% NaOMe solution (6.5 lit.) was added slowly. The reaction mixture was stirred for 3 hours. The solid was filtered and dried to provide 1.0 kg (67%) of 2,5-O-methylene-D-mannitol 18, m.p. 172°-173° C., [α]D −52° C. 1.18, CHCl3), TLC (silica gel), 1:4, methanol: chloroform, Rf=0.8. 1HNMR (D20): δ3.42 (m, 2H), 3.72 (m, 4 H), 3.97 (m, 2 H), 4.91 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH3:43])[C:27]1[C:28]([CH3:42])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([CH3:42])=[C:27]([N:26]([CH2:24][CH3:25])[CH3:43])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCN(C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 165.1.1) to give the title compound as a white foam. (HPLC: tR 2.26 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.32-8.29 (m, 1H), 8.13-8.09 (m, 2H), 7.99-7.94 (m, 1H), 7.61-7.58 (m, 1H), 7.35-7.32 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.97 (q, 2H), 2.71 (s, 31-1), 2.45 (s, 3H), 1.97 (s, 3H), 1.09 (t, 3H))
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[C:7]([OH:18])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]2)[CH:4]=[CH2:5].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:18][C:7]1[C:6]([CH:3]([CH2:2][O:1][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:4]=[CH2:5])=[CH:15][C:14]([CH3:16])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:17])[NH:12]2)(=[O:29])[CH3:28]
Reactant: C=CC(CO)c1cc(C)c2[nH]c(=O)ccc2c1O
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: C=CC(CO[Si](C)(C)C(C)(C)C)c1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
6-(1-Hydroxymethyl-2-propenyl)-5-hydroxy-8-methylcarbostyril (8.40 g, 34.3 mmol) was dissolved in pyridine (120 ml), to which tert-butyldimethylsilylchloride (7.5 g, 49.8 mmol) was added. The mixture was stirred at room temperature for 3 hours. Acetic anhydride (20 ml, 0.212 mol) was added to the reaction mixture, followed by stirring at room temperature for 90 minutes, then condensing under reduced pressure. The resultant residue was subjected to an azeotropic distillation along with toluene. The residue was extracted from chloroform--1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was purified by silica gel chromatography (chloroform: ether=1:1), and then the obtained crude crystals was recrystallized from chloroform--n-hexane. As a result, 6.00 g of the title compound was obtained as colorless powdery crystals (43.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[Cl:17][S:18](O)(=[O:20])=[O:19].O>ClCCCl>[F:1][C:2]1[CH:16]=[CH:15][C:14]([S:18]([Cl:17])(=[O:20])=[O:19])=[C:4]([CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (Intermediate 159, 0.497 g) in DCE (0.5 mL) was added to stirred, cooled chlorosulfonic acid (3 mL). The mixture was allowed to come up to room temperature and then heated at 70° C. for 3 hours. After cooling, the mixture was added carefully to a mixture of ice and water, then extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-10% to give 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]-benzenesulfonyl chloride (0.21 g) as a clear oil.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CO.CCOC(C)=O>[Si:21]([O:1][CH:2]([CH2:15][OH:16])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=C(NCC(O)CO)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(CO)CNC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of benzyl 2,3-dihydroxypropylcarbamate in DMF (0.1 M) was added TBDMSCl (2.2 eq.) and imidazole (2.5 eq.) at room temperature. After stirred for 20 h, the reaction mixture was worked up with EtOAc, which was washed with water and brine. The organic layer was separated, dried and concentrated to give the crude bis-silylated product, which was dissolved in methanol (0.16 M) followed by addition of p-toluenesulfonic acid (0.1 equiv.) at 0° C. The reaction mixture was stirred for 1.5 h at the same temperature. After quenched with saturated NaHCO3 aqueous solution, the reaction mixture was extracted with EtOAc, which was washed with water and brine. The organic layer was separated, dried, concentrated, and purified on silica gel with 0-100% EtOAc/Hexanes gradient elution to provide the pure benzyl 2-(tert-butyldimethylsilyloxy)-3-hydroxypropylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH3:23]C(C)(C)C(C(OC(C(=O)C(C)(C)C)=O)=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:19]([O:20][CH2:21][CH3:23])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[CH2:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)C(=O)C(=O)OC(=O)C(=O)C(C)(C)C
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(N)c(OC)cc4[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(N)c(OCC)cc4[C@H]3CC[C@]12C
Reaction time: 0.67 h
Yield: 42.1 %

Procedure:
Representative preparation of 3-formamide estrane derivatives: Preparation of 3-formamide-17-methylene-2-methoxyestra-1,3,5(10)-triene (Compound #88): 3-Amino-17-methylene-2-methoxyestra-1,3,5(10)-triene (293 mg, 0.99 mmol) was dissolved in chloroform (1 mL) and trimethylacetyl formic anhydride (170 mg, 1.30 mmol, prepared as in Vlietstra et al Recueil, 1982, 101, 460) was added. The mixture was stirred 40 min, after which, the solvent was removed under reduced pressure. The product was purified by titurating with hexanes and isolating the precipitate by decanting after the precipitate was centrifuged. Obtain 150 mg white powder (0.417 mmol, 42% yield). 1H NMR (300 MHz, CD3OD) δ 8.27 (s, 1H), 7.88 (s, 1H), 6.94 (s, 1H), 4.72-4.67 (m, 2H), 3.88 (s, rotamer 1) and 3.86 (s, rotamer 2, total 3H), 2.87-2.76 (m, 2H), 2.66-1.19 (m, 13H), 0.87 (s, 3H).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2[O:9][C:8]2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:43]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH:44]=[CH2:45]>C1(C)C=CC=CC=1.[Rh+]>[CH3:52][CH:51]([CH3:53])[CH2:50][CH2:49][CH2:48][CH2:47][O:46][CH2:43][CH2:44][CH2:45][CH:8]=[O:9].[CH3:45][CH:44]([CH2:43][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH:8]=[O:9]
Reactant: C=CCOCCCCC(C)C
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Rh+]
Solvent: Cc1ccccc1
Product: CC(C)CCCCOCC(C)C=O
Product: CC(C)CCCCOCCCC=O
Yield: 6.2 %
Yield: 62 %

Procedure:
Acetylacetanatodicarbonyl rhodium (I) (0.005 g, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.030 g, 0.05 mmol) were added to a 25 mL glass-lined autoclave and dissolved in toluene (3 mL). 1-(allyloxy)-5-methylhexane (2.0 g, 12.2 mmol) was added to the reactor and, following purging with nitrogen, the reaction mixture was subjected to hydroformylation conditions using a 1:1 molar ratio of hydrogen and carbon monoxide gas (30 bar, 60° C., 4 h) with vigorous stirring. The reaction mixture was directly chromatographed on silica gel (hexane/diethyl ether). The isolated products were Kugelrolhr distilled to give 4-[(5-methylhexyl)oxy]butanal (1.4 g, 7.5 mmol, chemical yield 62%) and 2-methyl-3[(5-methylhexyl)oxy]propanal (0.14 g, 6.2%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=O)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.[CH3:20][C:21]([NH2:26])([CH2:24][OH:25])[CH2:22][OH:23]>>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([CH2:18][NH:26][C:21]([CH3:20])([CH2:24][OH:25])[CH2:22][OH:23])=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: O=Cc1c2ccccc2c(CCCl)c2ccccc12
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NCc1c2ccccc2c(CCCl)c2ccccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 10-(2-chloroethyl)9-anthracenecarbaldehyde and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave 2-((10-(2-chloroethyl)-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 229°-231° (dec), (EtOH/Et2O), (C,H,Cl,N).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[CH:12]([C:14]1[NH:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[CH3:22])=O>>[CH3:22][C:15]1[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[NH:18][C:14]=1[CH:12]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)N(C)c2ccccc21
Yield: 88.6 %

Procedure:
1-Methyl-1,3-dihydroindol-2-one (147 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 250 mg (86%) of the title compound.
Reaction SMILES: [CH2:1]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Br:28][CH2:29][CH2:30][OH:31]>C(#N)C>[Br-:28].[OH:31][CH:30]([N+:25]1[CH:26]=[CH:27][N:23]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:24]=1)[CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCCn1ccnc1
Reactant: OCCBr
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCCCCCn1cc[n+](C(C)O)c1
Product: [Br-]
Temperature: 90 °C
Yield: 90.8 %

Procedure:
Approximately 3.76 g (0.010 mol) of 1-docosanylimidazole and about 1.45 g (0.012 mol) of 2-bromoethanol were dispersed into 100 mL of acetonitrile. The mixture was refluxed at 90° C. for approximately 24 hours under stirring condition, and subsequently cooled down to room temperature. The precipitate was filtered and washed with ethyl ether. The final product: 1-hydroxyethyl-3-docosanylimidazolium bromide was obtained after being dried in a vacuum oven. The yield was about 90.8% and the melting point was about 76.5° C. The spectra of 1H NMR (DMSO-d6 as the solvent, δ, ppm) was 9.107 (N—CH—N, s, 1H), 7.743 (N—CH—CH, s, 1H), 7.712 (N—CH—CH, s, 1H), 4.192 (N—CH2—CH2—OH, t, 2H), 4.141 (N—CH2—CH2—OH, t, 2H), 3.706 (N—CH2—C21H43, t, 2H), 1.754 (N—CH2—CH2—C20H41, m, 2H), 1.202 (N—CH2—CH2—(CH2)19, m, 38H), 0.822 (CH3, t, 3H).