Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=[O:11])[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30]O)[CH2:28][OH:29].C(OCC)(=O)C.CCCCCC>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:28][O:29][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH2:22][C@H:2]4[OH:1])[CH2:5][CH2:6]2)[CH3:9])[O:11][CH2:30]1
Reactant: CC(C)(CO)CO
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
In 200 ml of methylene chloride were dissolved 5.00 g (14.6 mmoles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid and 20 g of molecular sieve 4A 1/16. The mixture was stirred gently at room temperature for 12 hours. From the reaction mixture thus obtained, the molecular sieve was filtered off and the solvent in the filtrate was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:10, v/v) to give 3.14 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7α-hydroxypregna-1,4-dien-3-one (yield: 50%).
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=2[CH:22]=1)[C:10]#[C:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.O>ClCCl>[CH3:31][C:27]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:34])[C:23]2[CH:22]=[C:21]([CH2:9][C:10]#[C:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (8.1 mmol) of BF3 ·Et2O (48%) and 50 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. 2.6 ml (16.2 mmol) of triethylsilane are added at -20° C., followed by a solution of 1 g (2.7 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid in 30 ml of dichloromethane and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified on a column of silica eluted with dichloromethane. After evaporation of the solvents, 780 mg (82%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid are collected, with a melting point of 167-8° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.O1CCCC1.[OH-].[Li+].O[Li].O>O>[F:31][C:27]1[C:28]([F:30])=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]3[CH:14]=[C:15]4[C:10]([CH:9]=[CH:8][N:7]4[CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:11][CH:12]=3)=[CH:19][CH:20]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: [Li+]
Agent: [Li]O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CCC(=O)O)c3c2)cc1
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester (24 mg, 0.051 mmol, 1 eq.) was added tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide (LiOH—H2O (4.5 mg, 0.1 mmol, 2.2 eq.). The reaction was stirred and at room temperature for 2 and then DOWEX resin (50WX4-400, acid washed, 2 g) was added. The mixture was stirred at room temperature, filtered, dried, and then lyophilized from acetonitrile/water to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid as an off-white solid (23 mg, 98%). LC-MS (ES) calculated for C25H21F2NO4, 437.12; found m/z 438 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:5](=[CH:6][C:7]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]=3[C:16]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[C:8]3[C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[S:11][C:7]=3[CH:6]=[C:5]3[C:17]=2[CH:18]=[CH:19][C:3]([OH:2])=[CH:4]3)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2c3ccc(OC)cc3cc3sc4ccccc4c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2c3ccc(O)cc3cc3sc4ccccc4c23)cc1
Reaction time: 3.5 h

Procedure:
To a cold (-75° C.) solution of 8-methoxy-11-(4-methoxy-phenyl)-benzo[b]naphtho[2,3-d]thiophene (1.92 g, 5.18 mmol) in anhydrous methylene chloride was added a solution of boron tribromide (1 M in methylene chloride, 6.74 mL, 6.74 mmol, 1.3 eq) dropwise over a period of 18 minutes. After stirring in the cold for 3.5 hours and at ambient temperature for approximately 19 hours the reaction mixture was quenched with water (100 mL), diluted with methylene chloride (50 mL) and the organics were extracted with diethyl ether (1×100 mL, 1×75 mL). The extracts were combined, washed with brine, and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (74/26 petrolem ether/ethyl acetate) and dried at 92° C. overnight to the title compound as an off-white solid (1.07 g, 91%): mp 233-235° C.; NMR (DMSO-d6); δ 9.91 (broad s, 1H), 9.77 (broad s, 1H), 8.30 (s, 1H), 7.88 (d, J=8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.35 (ddd, J=8, 8, 1 Hz, 1H), 7.23 (d, J=2 Hz, 1H), 7.15 (d, J=8 Hz, 2H), 7.09 (ddd, J=8, 8, 1 Hz, 1H), 7.06-7.00 (multiplet containing a doublet at 7.05, J=8 Hz, 3 H), 6.71 (d, J=8 Hz, 1H); MS (+FAB): [M+] 343; Anal. Calc. for C22H14O2S: C, 77.17, H, 4.12, N, 0.00. Found: C, 76.43, H, 3.82, N, 0.01.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cnccn1)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (227 mg, 0.839 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (207 mg, 70.9%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[OH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:4]2
Reactant: O=Cc1cccc(O)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cccc(O)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2,3-dihydroxybenzaldehyde (95.8 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 8-hydroxy-3-carboxy-coumarin.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)(=O)C>[N+:16]([C:5]1[CH:4]=[C:3]2[CH:2]=[CH:1][CH:10]=[C:9]3[C:8]2=[C:7]([CH:6]=1)[C:14](=[O:15])[N:19]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]3=[O:13])([O-:18])=[O:17]
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O

Procedure:
The compound was prepared from 3-nitro-1,8-naphthalic anhydride (1.00 g, 4.1 mmol) and 4-aminobutyric acid (0.42 g, 4.1 mmol) in 100 mL glacial acetic acid using the general procedure shown in Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][C:16](O)=[O:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:16](=[O:17])[CH2:15][C:11]2[S:10][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1nccs1
Reactant: Cc1c(N)cccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1NC(=O)Cc1nccs1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of 3-bromo-2-methylaniline (0.764 mL, 6.20 mmol), 1,3-thiazol-2-ylacetic acid (0.74 g, 5.17 mmol) and DIEA (1.63 mL, 9.30 mmol) in DMF (15 mL) was treated with HATU (2.36 g, 6.20 mmol). After stirring overnight, the mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl followed by brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give N-(3-bromo-2-methylphenyl)-2-(thiazol-2-yl)acetamide as a white solid (0.681 g, 42% yield). 1H NMR (400 MHz, chloroform-d) δ 9.84-9.65 (m, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.07 (t, J=8.0 Hz, 1H), 4.18 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[N:7]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NC(C)(C)CC)C>CN(C=O)C.C(OCC)C.O>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:26][CH:27]=3)[CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(CCn1ncc2ccc(N)cc21)OC
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(CCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3,3-dimethoxypropyl)-1H-indazole-6-ylamine (1.32 g, 5.60 mmol), 4-phenoxyphenylacetic acid (1.34 g, 5.88 mmol), N-methyl morpholine (1.47 mL, 13.4 mmol), HOBt (945 mg, 7.0 mmol), and ethyldimethylpropylcarbodiimide hydrochloride (1.34 g, 7.0 mmol) in DMF (28 mL) was stirred at room temperature for 3 hours followed by the addition of H2O (40 mL) and diethyl ether (30 mL). The layers were separated, and the aqueous was extracted with diethyl ether (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated under reduced pressure and purified by MPLC (SiO2, 1:1 hexane:ethyl acetate to 1:3 hexane:ethyl acetate) to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.05 (m, 2 H), 3.22 (m, 6 H), 3.68 (s, 2 H), 4.29 (m, 3 H), 6.99 (m, 4 H), 7.14 (m, 2 H), 7.38 (m, 4 H), 7.66 (m, 1 H), 7.97 (s, 1 H), 8.12 (s, 1 H), and 10.34 (s, 1 H); MS (ESI) 444 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=[CH:30][C:31](O)=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[CH:30]/[C:31]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:21][CH:20]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c2ccccc12
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c4ccccc34)nc2n(CCC)c1=O
Yield: 56.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.33 g (14.6 mmol) of 3-(4-methoxynaphthyl)acrylic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.12 g (yield 56%) of Compound 61 as yellow needles.
Reaction SMILES: S([NH:11][C:12]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=1[OH:26])=[O:15])(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O>O>[NH2:11][C:12]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[C:17]=1[OH:26])=[O:15]
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C)cc2)c(O)c1OC
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)c2cc(Cl)ccc2N)c(O)c1OC
Yield: 76.7 %

Procedure:
A mixture of 2-tosylamino-5-chloro-2'-hydroxy-3', 4'-dimethoxybenzophenone (5.89 g) and 70% sulfuric acid (50 ml) was heated for 1 hr. at 90° C. The whole was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by a column chromatography on silica gel and recrystallized from a mixture of ether and hexane to give 2-amino-5-chloro-2'-hydroxy-3',4'-dimethoxybenzophenone as colorless prisms (3.01 g, 76.8%). m.p. 112°-115° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OCc3ccccc3)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one (Example 1d) in 65 ml of dimethylformamide is mixed with 3.3 ml of benzyl chloride, 8.7 g of cesium carbonate and 400 mg of sodium iodide, and it is stirred overnight at room temperature. The reaction mixture is poured into water, shaken out with ethyl acetate, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate. 7.26 g of 7α-(5-acetoxypentyl)-3-benzyloxy-estra-1,3,5(10)-trien-17-one is obtained as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1ccc(Br)cc1C=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(C=O)cc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
5-Bromo-2-methoxybenzaldehyde (29.65 g, 138 mmol) was added to stirred concentrated sulfuric acid (160 mL) at −15° C. Nitric acid (70% w/w) (16 g) was added dropwise. Further stirring was allowed for 15 mins at this temperature before the mixture was poured onto crushed ice (2 L). The resulting precipitate was collected by filtration and partitioned between dichloromethane (800 mL) and saturated sodium hydrogen carbonate (1 L). The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound (20.5 g) as a crude solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.C(Cl)Cl.CO.Cl>[CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CN(C2CCc3cc(-c4noc(-c5ccc(CC(C)C)cc5)n4)ccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2nc(-c3ccc4c(c3)CCC4N3CC(C(=O)O)C3)no2)cc1
Yield: 76.9 %

Procedure:
A solution of 4.5 g (8.1 mmol) of methyl (±)-1-(5-(5-(4-(2-Methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate, Enantiomer 1 (from Example 17, Step A) in 25 mL of MeOH was treated with 3.0 mL of 5.0 N NaOH and the resulting mixture was heated at reflux for 3 h. The mixture was cooled, diluted with 4:1 v/v CH2Cl2/MeOH and neutralized with concentrated HCl. The solids were filtered and the filtrate was concentrated. Chromatography on a Biotage 75S cartridge using 4 L of 17:3 v/v CH2Cl2/MeOH+1% NH4OH, then 4 L of 3:1 v/v CH2Cl2/MeOH+1% NH4OH afforded 2.60 g of the title compound: 1H NMR (500 MHz, DMSO) δ 8.08 (d, J=8.0 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 3.85–3.88 (m, 1H), 3.50 (app t, J=7.5 Hz, 1H), 3.39 (app d, J=7.5 Hz, 2H), 3.26 (app t, J=7.5 Hz, 1H), 3.13–3.18 (m, 1H), 2.97–3.30 (m, 1H), 2.81–2.87 (m, 1H), 2.57 (app d, J=7.5 Hz, 2H), 2.49 (t, J=1.5 Hz, 1H), 2.03–2.11 (m, 1H), 1.83–1.89 (m, 1H), 0.88 (d, J=6.5 Hz, 6H); ESI-MS 418.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(O)c1
Yield: 99 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid (4.3 g, 0.028 mole) in methanol (30 mL) was added H2SO4 (1 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed, the residue was washed with H2O, and extracted three times with EtOAc (ethyl acetate). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 4.7 g (99% yield) of the title compound as an oil. MS (ESI) 167.0(M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([O:24][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1cccnc1
Yield: 69.6 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (404 mg), which is obtained in a similar manner to that described in Reference example 39(a), 3-hydroxypyridine (227 mg), triphenylphosphine (938 mg) and solution of diethylazodicarboxylate in toluene (40%, 0.65 ml) and the reaction mixture was treated to afford the desired compound (345 mg) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[NH3:15]>C(O)(C)C>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(OCCC2CO2)cc1
Reactant: N
Solvent: CC(C)O
Product: N#Cc1ccc(OCCC(O)CN)cc1
Reaction time: 24 h
Yield: 93 %

Procedure:
4-[2-(2-Oxiranyl)ethoxy]benzonitrile (38.5 g, 204 mmol; from step (d) above) was mixed with NH3 (1200 mL, conc.) and isopropanol (450 mL). The mixture was stirred at r.t for 24 h. The solid (by-product) was filtered off and the solvents were evaporated, to give 39.1 g (93%) of sub-title compound.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[Li]CCCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C@@H:2]([CH2:9][CH3:10])[CH2:3][C:4]1[S:5][C:6]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:7][CH:8]=1
Reactant: CC[C@H](C)Cc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1ccc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-2-(2-methylbutyl)thiophene (4.27 g, 27.7 mmol) in dry THF (100 mL) was cooled to −78° C., and a solution of n-BuLi (2.5 M, 16.6 mL, 41.5 mmol) was then added slowly. This mixture was stirred at −78° C. for additional 10 minutes, and then allowed to warm to room temperature and stirred at room temperature for 30 minutes, before it was cooled back to −78° C. A solution of trimethylstannyl chloride (1.0 M, 43 mL, 43.0 mmol) was added slowly. This mixture was stirred at −78° C. for 2 hours, and then allowed to warm to room temperature, and stirred at room temperature overnight. The reaction was quenched by water (20 mL), and the reaction mixture was diluted with hexane, washed with water, dried over Na2SO4, and concentrated on a rotary evaporator, leading to a slightly yellow oil (8.7 g, 99.1%), which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:17])=[N:13]2)=[CH:8][CH:7]=1.[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:17]=[O:19])=[N:13]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2ccc(C)nc2c1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1ccc2ccc(C=O)nc2c1C
Yield: 70 %

Procedure:
To 7-(2-methoxyethoxy)-2,8-dimethylquinoline (90 mg, 0.39 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (52 mg, 0.47 mmol) and the reaction was heated to reflux for 1 hour. After cooling, the reaction was filtered and the solids washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-8-methylquinoline-2-carbaldehyde (67 mg, 70% yield) as a tan solid.