Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:10])[C:3]=1[OH:11].[O:12]1[CH2:16]CC[CH2:13]1.C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:13][O:12][CH3:16])[C:3]=1[O:11][CH2:26][O:27][CH3:28]
Reactant: COCCl
Reactant: C1CCOC1
Reactant: COc1ccc(Br)c(O)c1O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)ccc(OC)c1OCOC
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of 1-bromo-2,3-dihydroxy-4-methoxy-benzene (5.0 g) and anhydrous tetrahydrofuran (20 mL) at 0° C. under argon was added diisopropylethylamine (8.0 mL). The solution was stirred for 15 min, methyloxymethyl chloride (3.5 mL) was added, and the reaction mixture stirred for 3 hours. The solution was poured into water (250 mL), extracted with dichloromethane and the solvent removed in vacuo to provide an orange oil. The oil was purified by flash column chromatography (hexane-ethyl acetate, 2:1) to yield a clear oil (6.4 g, 91%): EIMS m/z 308 (M+, 81Br), 306 (M+, 79Br), 232, 230, 45; IR (neat, cm−1) vmax 2963, 2836, 1221, 1159, 1084, 966; 1H NMR δ 7.25 (1H, d, J=9.0 Hz, H5), 6.61 (1H, d, J=9.0 Hz, H4), 5.20 (2H, s, OCH2), 5.13 (2H, s, OCH2), 3.84 (3H, s, OCH3), 3.66 (3H, s, OCH3), 3.59 (3H, s, OCH3); 13C—NMR (75.5 MHZ) δ 153.31, 148.24, 140.05, 127.49, 108.94, 108.73, 99.39, 98.73, 58.14, 57.46, 56.11. Anal. Calcd. For C11H15O5Br: C, 43.02; H, 4.92. Found: C, 42.86; H, 4.93.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 98445.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 24.0 g, 0.48 mol) was added portionwise to a stirred solution of anhydrous benzyl alcohol (64.5 g, 0.60 mol) in THF (1.0 L). After the mixture was stirred for 1 h, a solution of 1-bromo-3,5-difluorobenzene (76.8 g, 0.40 mmol) in THF (100 mL) was added dropwise over a period of 1 h. The reaction was stirred at room temperature for 2 d. Water (400 mL) was added and the THF was removed in vacuo. The aqueous layer was extracted with hexane (3×150 mL). The combined organic extracts were washed with 2N NaOH (2×100 mL) then, dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (110.7 g, 98%) as a light yellow oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.Cl.[CH2:17]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH3:18].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:17]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[CH:25]([NH:26][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:18]
Reactant: C[Si](C)(C)CCCc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(CCC[Si](C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
2,4-dichloro-6-[3-(trimethylsilyl)-propyl]pyrimidine (1 gram), L-leucine-3-ethoxypropylamide hydrochloride (1 gram) and N,N-diisopropylethylamine (2.3 mL) were stirred for 17 h in 20 mL dimethyl sulfoxide at 55° C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 3/1) provided 978 mg of 2-(2-chloro-6-[3-trimethylsilylpropyl]pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxypropyl)amide.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][C:14](=[O:16])[CH3:15]>C(O)C.O.CN(C=O)C.[Fe]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[C:5]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1c(N)cccc1Br
Reaction time: 6 h

Procedure:
Iron powder (2.92 g, 52.32 mmol) and ammonium chloride (2.3 g, 43.6 mmol) in ethanol (40 mL) and water (20 mL) were added to a solution of N-(2-bromo-6-nitrophenyl)acetamide [Edlin et al., New Journal of Chemistry 1999, 23, 819–826] (2.26 g, 8.72 mmol) in DMF (20 mL) and the mixture was heated at reflux. After 6 h, the reaction was filtered through a celite pad, washed with acetone, and concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[N:13]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:12]2=[O:28])(C)(C)C.[ClH:30]>CO.C(Cl)Cl.CCOCC>[ClH:30].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[N:13]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:12]2=[O:28]
Reactant: Cc1nc2ccc(CNC(=O)OC(C)(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 8 h

Procedure:
To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-carbamic acid tert-butyl ester (3.5 g, 8.7 mmol) in methanol (36 mL) and methylene chloride (36 mL), was added 2 M HCl in ether (102 mL), and the mixture was stirred overnight. The solvent was evaporated, and the residue was stirred in ether (100 mL) for 2 hours. The suspension was filtered to give 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride as a light yellow solid (3.2 g, 109% crude yield). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)=[CH:13][C:12]=1[F:18]
Reactant: Cc1cc(C)nc(Br)c1
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)nc(Oc2ccc(Br)c(F)c2)c1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
A mixture of 2-bromo-4,6-dimethylpyridine (1 g, 5.4 mmol), 4-bromo-3-fluoro-phenol (1.03 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) was heated at 150° C. (oil bath temperature) in a sealed tube for 7 days. After cooling to room temperature the mixture was diluted with DCM and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 7 (1.1 g, 53%).
Reaction SMILES: O.C(OCC)(=O)C.[Br:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]3[CH:29]=[CH:30][N:31]=[C:19]23)=[C:11]([F:32])[CH:10]=1>[Fe].C(O)(=O)C>[NH2:15][C:14]1[C:9]([Br:8])=[CH:10][C:11]([F:32])=[C:12]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]3[CH:29]=[CH:30][N:31]=[C:19]23)[CH:13]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Br)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br

Procedure:
To a mixed solution of water (100 ml), ethyl acetate (50 ml) and acetic acid (50 ml) was added 8-(4-bromo-2-fluoro-5-nitrophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (12.5 g) synthesized in Example 16 and iron powder (8.0 g) and heated to reflux for 3 hours. The reaction solution was filtered through Celite and then the Celite was washed with heated ethyl acetate. The combined filtrate and washing was washed with water, saturated sodium hydrogencarbonate and water in this order, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure after removing a portion adjacent to the original point of the short column of alumina. The thus obtained solid was recrystallized from isopropyl alcohol/isopropyl ether=1/9 to give the compound of interest (9.3 g).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH2:26]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([N:12]2[CH2:25][CH2:24][CH2:23][N:22]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:2])=[O:26])[CH2:21][CH2:20][N:19]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: C1CNCCNCCCNCCNC1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A solution of tosyl chloride (8.1 g, 43 mmol) in chloroform (300 mL) was added dropwise over a period of 2 h to a solution of 1,4,8,11-tetraazacyclotetradecane (4.28 g, 21 mmol) in chloroform (150 mL) and triethylamine (18 mL) kept at 45° C. After the mixture stood at room temperature overnight, water (40 mL) was added with stirring. The organic layer was separated, dried (Na2SO4), and evaporated to dryness. The solid residue was dissolved in hot methanol (40 mL) and cooled to room temperature to yield a white oil. The methanol solution was decanted, and the oil triturated with more methanol to give white crystals of 7-H2O of the title compound (5.5 g, 33%). A second crop of the tritosyl derivative was obtained by evaporating the mother liquor of the first crop to dryness, dissolving the resulting sticky oil in chloroform (150 mL) and triethylamine (10 mL), and adding to the solution tosyl chloride (2 g, 10 mmol) dissolved in chloroform (50 mL) at 45° C. in 40 min. Standard workup of the solution gave white crystals of 7-H2O of the title compound (2.1 g, 13%). MS (ESP) m/z 663 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[CH:14]=[C:13]([Cl:15])[C:10]([C:11]#N)=[CH:9][N:8]=1.[OH2:16]>C(=O)(O)[O-].[Na+]>[NH2:6][C:7]1[CH:14]=[C:13]([Cl:15])[C:10]([C:11]([OH:2])=[O:16])=[CH:9][N:8]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: O
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cc(Cl)c(C(=O)O)cn1
Temperature: 100 °C

Procedure:
Concentrated sulfuric acid (98%, 0.5 mL) was added dropwise to a stirred suspension of compound iii (0.020 g, 0.130 mmol) in water (1 mL). The reaction mixture was heated to 100° C. for 18 h, cooled to room temperature and added dropwise to a slurry of ice in saturated sodium bicarbonate solution (2 mL). The pH after addition was pH-2. The resulting precipitate was filtered, washed with water (2 mL) and air-dried to give compound iv. (0.019 g, 0.110 mmol, 84%) as a colourless powder, [M+H]+ m/z=173.0.
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:23])[C:20]=1[CH2:21]O)[CH2:6][CH2:7][CH3:8].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:5]([N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:23])[C:20]=1[CH2:21][Cl:3])[CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1ccnc1Sc1cncc(Cl)c1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1ccnc1Sc1cncc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SOCl2 (27 μL, 0.37 mmol) was added dropwise to a stirred solution of [3-(1-butyl-1H-imidazol-2-ylsulfanyl)-5-chloro-pyridin-4-yl]-methanol (22 mg, 0.74 mmol) in DCM (4 mL). After stirring for 1 h at room temperature, saturated aqueous Na2CO3 solution (5 mL) and DCM (5 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 316.1 [M+H+].
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:43]([O:47][C:48](=[O:59])[NH:49][CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48](=[O:59])[NH:49][CH2:50][C:51]([N:52]1[CH2:53][CH2:54][N:55]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:21]=2[Cl:20])[CH2:56][CH2:57]1)=[O:58])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
HOBt (125 mg, 0.93 mmol) and DIPEA (207 mg, 2.2 mmol) were added to a stirred solution of 2,5-dichloro-benzoic acid (141 mg, 0.74 mmol) in DMF (2.5 mL). The mixture was then cooled to 10° C. and EDCI.HCl (178 mg, 0.93 mmol) followed by (2-oxo-2-piperazin-1-yl-ethyl)-carbamic acid tert-butyl ester (200 mg, 0.82 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification using column chromatography (silica gel (60-120 mesh) using 30% ethyl acetate in hexane as the eluent) afforded {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester as a solid in 91.2% yield. LC-MS purity: 99.48%.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][N:38]([CH2:41][C:42](O)=[O:43])[C:37](=[O:45])[N:36]=1)=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:42](=[O:43])[CH2:41][N:38]2[CH:39]=[CH:40][C:35]([NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])=[N:36][C:37]2=[O:45])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: CSCCOC(=O)Nc1ccn(CC(=O)O)c(=O)n1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(2-methylthioethoxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.72 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.01 (t, 1H), 4.82 (s, 1.2H), 4.71 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.26 (t, 2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H), 2.73 (t, 2H), 2.11 (s, 3H).
Reaction SMILES: OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.CN1CCOCC1.ClC(OCC(C)C)=O.N[C:33]1[CH:34]=[C:35]([CH:44]=[CH:45][CH:46]=1)[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>CN(C=O)C>[C:36]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:37])[C:35]1[CH:44]=[CH:45][CH:46]=[CH:33][CH:34]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
The D-biotin (50 mg, 2.05 mmol) is solubilized in 23 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (295 μl, 2.67 mmol) and isobutyl chloroformate (420 μl, 3.28 mmol) are successively added. The mixture is kept stirred for 30 min, and then 3-aminobenzophenone (605 mg, 3.07 mmol) and N-methylmorpholine (240 μl, 2.17 mmol) in 7 ml of DMF are added. The solution is maintained stirred at 0° C. for 2 h, and then evaporated to dryness. The residue is taken up in 1 ml of MeOH, and then 25 ml of water are added. The precipitate obtained is filtered, washed with water and then with ether to give 810 mg (93%) of crude product 1d. Recrystallization from the MeOH—H2O pair gives 1d (630 mg, 72%) in the form of a white powder.
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][C@@H:8]([O:30]C=O)[C@@H:9]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1)=[O:2].[CH:33]([O:35][C@@H:36]1[CH2:59][CH2:58][C@@:57]2([CH3:60])[C@H:38]([CH2:39][C@H:40](OC=O)[C@@H:41]3[C@@H:56]2[CH2:55][CH2:54][C@@:53]2([CH3:61])[C@H:42]3[CH2:43][CH2:44][C@@H:45]2[C@H:46]([CH3:52])[CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:37]1)=[O:34]>>[CH:1]([O:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][C:8](=[O:30])[C@@H:9]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1)=[O:2].[CH:33]([O:35][C@@H:36]1[CH2:59][CH2:58][C@@:57]2([CH3:60])[C@H:38]([CH2:39][CH2:40][C@@H:41]3[C@@H:56]2[CH2:55][CH2:54][C@@:53]2([CH3:61])[C@H:42]3[CH2:43][CH2:44][C@@H:45]2[C@H:46]([CH3:52])[CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:37]1)=[O:34]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](OC=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](OC=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following the procedures of Example 3 but substituting equivalent amounts of 3α,7α-diformyloxy-5β-cholan-24-oic acid; 3α,7β-diformyloxy-5β-cholan-24-oic acid; or 3α-formyloxy-7-keto-5β-cholan-24 oic acid for the 3α-formyloxy-5β-cholan-24-oic acid there is obtained respectively, 3α,7α-Diformyloxy-5β-cholan-24-oyl chloride; 3α,7β-diformyloxy-5β-cholan-24-oic acid; 3α-formyloxy-7-keto-5β-cholan-24-oyl chloride.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:12])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(C)c1[N+](=O)[O-]

Procedure:
Nitromesitylene (20.0 g) is added to a mixture of N-bromosuccinimide (11.7g, 2 equivalents) and azobisisobutyronitrile (10 mg) in carbon tetrachloride (1000 ml). The flask is illuminated with a bright incandescent bulb (controlled by a Variac) with stirring until reflux occurs; an additional heat source is required. After 4 hours the reaction mixture is cooled, evaporated to a residue and partitioned between water and dichloromethane. The organic phase is separated, dried, and evaporated to a residue which is purified by column chromatography on silica gel by gradient elution: benzene/hexane (1:9 to 4:1). The purified product, mostly 4-bromomethyl-2,6-dimethylnitrobenzene, is isolated as an orange oil, 36.8 g.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[Br:6][CH2:7][CH2:8][NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)C>[Br:6][CH2:7][CH2:8][N:9]1[CH:2]=[CH:1][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C=C(CC(=O)OC)NCCBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
Sodium acetate (41.0 g, 500 mmol) was added to the 2-bromoacetaaldehyde solution, and stirred for 5 minutes, at which point the solution had a pH of 6. The flask was placed in a cool tap water bath and dimethyl 3-(2-bromoethylamino)-2-pentenedioate (20.0 g, 71 mmol) was added, followed by isopropanol (40 mL), and the solution was stirred at room temperature (25° C.). Within about 35 minutes, all the solids had dissolved, and a precipitate started forming within 90 minutes. Stirring was continued at room temperature for 20 hours, and the solution then cooled to 0° C. and stirred at that temperature for 1 hour, then filtered through a coarse frit. The precipitate was washed with ice-cold water (400 mL) and ice-cold isopropanol (150 mL) and dried, to give 15.7 g (72% yield) of crude methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate as a light tan solid, m.p. 129°-130.5° C., NMR (CDCl3): δ:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:2]1=2.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:2]1=2
Reactant: CI
Reactant: CCOC(=O)Cc1ccc2c(c1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2c(c1)OCCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)acetate (257 mg, 1.16 mmol) in DMF (2 mL) was added NaH (50 mg, 1.25 mmol) and iodomethane (167 mg, 1.18 mmol) in DMF (0.5 mL) at 0° C. The reaction mixture was stirred for 1 hrs at 0° C. then diluted with H2O (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:6) as eluant.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19]=COCC)[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:19]=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC=C=C(C#N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2cc(C(=O)O)ccc2C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 478 mg, 2.36 mmol, 1.0 eq) in 20 mL of ethanol were added ethyl(ethoxymethylene)cyanoacrylate (399 mg, 2.36 mmol, 1.0 eq) and triethylamine (329 μL, 2.36 mmol, 1.0 eq) and the mixture was heated at 65° C. for 5 hrs. After standing at room temperature overnight, additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78 mmol, 0.3 eq) and triethylamine (110 μL, 0.78 mmol, 0.3 eq) and heated for 2.5. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproducts followed by EtOAc and 9/1 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR 1.87 min; MS m/z 290.1 [M+H]+; 1H NMR (CD3OD), δ 8.08 (d, J=7.0 Hz, 1 H), 7.93 (s, 1 H), 7.76 (s, 1 H), 7.54 (d, J=8.0 Hz, 1 H), 4.29 (q, J=7.1 Hz, 2 H), 2.19 (s, 3 H), 1.35 (d, J=7.1 Hz, 3 H), ppm; 13C NMR (CD3OD), δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5, 128.6, 93.8, 58.8, 15.8, 12.9 ppm.