Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:45][C:46]1[S:50][C:49]([C:51]([N:53]2[CH2:58][C:57]3([CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[O:56][CH2:55][CH2:54]2)=[O:52])=[CH:48][CH:47]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:61]2[CH2:62][CH2:63][C:57]3([O:56][CH2:55][CH2:54][N:53]([C:51]([C:49]4[S:50][C:46]([CH3:45])=[CH:47][CH:48]=4)=[O:52])[CH2:58]3)[CH2:59][CH2:60]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.426 g) in MeCN (2 mL) was added dropwise to a solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.154 g) and triethylamine (0.15 mL) in MeCN (5 mL) at RT under argon. The resulting mixture was stirred at 60° C. under argon for 16 h, and then at 80° C. for an additional 3 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The brown solid was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2([CH3:21])[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16]C)[CH:13]=3)[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:7]2([CH3:21])[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([OH:16])[CH:13]=3)[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 175 °C

Procedure:
2-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (4.94 g., 0.015 mole) is mixed with pyridine hydrochloride (50 g.) and the mixture is heated at 175° C. for 1 hour, then poured into water (500 ml.) and the product is collected and crystallized from ethanol:water, 2:1 to obtain 2-phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 194°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][C:31](=[O:37])[N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:26]=[C:25]([CH3:38])[C:22]=1[CH:23]=O>CO>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[C:25]([CH3:38])=[CH:26][C:27]([O:29][CH2:30][C:31](=[O:37])[N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:28][C:21]=4[CH3:20])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cc(OCC(=O)N2CCCC2)cc(C)c1C=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OCC(=O)N5CCCC5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzamide (0.8 mL in 0.2 M DMSO solution), 2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.8 mL in 0.2 M toluene solution) and FeCl3 (0.4 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge. United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-[2,6-dimethyl-4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethyl-phenyl)-amide: MS (m/z) 497 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[CH3:38])=[O:22])[CH2:17][CH2:16]1)[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:26]1[CH:27]=[CH:28][C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]3)=[O:22])=[C:24]([CH3:38])[CH:25]=1)[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: CCN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN1CCN(C(=O)c2ccc(-c3cnc4cccc(Br)c4n3)cc2C)CC1
Temperature: 105 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-chloro-quinoxaline (Step 1.4, 298 mg, 1.226 mmol), (4-Ethyl-piperazin-1-yl)-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (439 mg, 1.226 mmol), K3PO4 (532 mg, 2.450 mmol) and Pd(PPh3)4 (43.8 mg, 0.0368 mmol). After several cycles of vacuum/purge with argon, 5 ml of dry DMA are added. The reaction mixture is then heated to 105° C. for 4 h. After cooling, the suspension is poured onto 70 ml de-ionized water and filtered. The cake is re-taken in EtOAc, washed with saturated brine and dried over Na2SO4. After filtration, the mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>0:1) to afford the title compound as a pale brown foam, Rt=0.833 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 439 (M+1, 79Br)+.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)C1C=CC=CC=1>CO.[Pd]>[C:32]([O:31][C:29]([N:18]([CH2:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH2:10])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCc1ccc(F)cc1)C[C@@H]1CCCC[C@H]1N
Yield: 65 %

Procedure:
The product from Step h (0.7 g, 1.9 mmol) was dissolved in 100 mL MeOH and added carefully to 0.1 g of 10% Pd/C under N2. The mixture was hydrogenated in a Parr shaker at 50 PSI overnight. Filtration through fiberglass filter paper under N2 and under vacuum yielded 0.45 g of a clear colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:56][CH2:57][C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=2)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: NCc1cccc(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.8 %

Procedure:
To a solution of 3-Cyano-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.62 mmol) in anhydrous DMF (8 mL) was added triethylamine (0.26 mL, 1.86 mmol), HBTU (0.28 g, 0.74 mmol), HOBT (100 mg, 0.74 mmol), and 3-Aminomethyl-phenol (114 mg, 0.92 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.033 g, 17% yield).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O>C(#N)C>[NH2:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate was deprotected with a solution of pTSOH.H2O in acetonitrile as described in the preceding experiment to provide the title compound which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11](=[O:14])[CH2:12][CH3:13].[F:15]OC(F)(F)F>>[F:15][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:11](=[O:14])[CH2:12][CH3:13])[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: FOC(F)(F)F
Reactant: CCC(=O)c1c(OC)cccc1OC
Product: CCC(=O)c1c(OC)ccc(F)c1OC

Procedure:
The electrophilic fluorination of compound IV can be performed by passing trifluoromethyl hypofluorite into a stirred mixture of the compound in Freon at -78° C. The reaction is monitored frequently by thin layer chromatography to avoid over-fluorination. The crude product from the reaction is purified by column chromatography to provide 1-(3-fluoro-2,6-dimethoxyphenyl)propan-1-one V which is then reduced with borane in the presence of boron trifluoride in boiling tetrahydrofuran to give 1-fluoro-2,4-dimethoxy-3-propylbenzene VI in excellent yield. Acylation of V with an alkanoyl chloride under conventional Friedel-Crafts, conditions provides a compound of general structure VII which on treatment with boron tribromide in methylene chloride at -78° C. is demethylated to yield the afore-mentioned 1-(2,4-dihydroxy-5-fluoro-3-propylphenyl)alkan-1-one of general formula VIII.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=3[N:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]3=[O:35])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1ccccn1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-n2ccccc2=O)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-hydroxypyridine as in Example 45 to afford 0.010 g (8%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO5F3 523, found 524 (M+1, 100%).
Reaction SMILES: [C:1]1(=[O:16])[N:5](C2NC=CC=2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClC(Cl)C>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([C:4]1[N:5]([N:5]2[C:1](=[O:16])[C:2]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:3]3[C:4]2=[O:11])[CH:1]=[CH:2][CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1c1ccc[nH]1
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(Cl)cc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Yield: 163.7 %

Procedure:
To a suspension of phthalimidopyrrole (748.6 g) and 2,4-dichlorobenzoyl chloride (1109.1 g) in 3.5 L of dichloroethane was added 707.3 g of K-10 Montmorillonite clay. The resulting mixture was stirred at reflux for 48 hrs, then filtered and concentrated to a semisolid. The semisolid was triturated with a large quantity of ether and collected to yield 1112.5 g of powder. The ether wash was concentrated to give 162.0 of a residue. This was purified by high performance liquid chromatography (HPLC hereinafter, silica, dichloromethane) and recrystallized from absolute ethanol to yield 37.26 g of crystals, mp 152°-153° C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N:6]1[CH:7]=[CH:8][C:3]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:16])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Reaction time: 1 h

Procedure:
To a 3-necked 500 mL RB flask fitted with a mechanical stirrer were charged 4-cyanopyridine (10.4 g, 0.1 mole) and benzophenone (18.2 g, 0.1 mole). Dry liquid ammonia was carefully added (250 mL) and the starting materials were dissolved. Sodium metal was then added (5.0 g, 0.22 mole) slowly in small pieces. The reaction mixture was stirred for 1 hour and the ammonia allowed to evaporate. Toluene (150 mL) and water (150 mL) were then added to the residue and the resulting mixture was stirred for 15 minutes. The precipitated product was filtered and washed with water, giving 4-pyridyl diphenyl carbinol.
Reaction SMILES: [CH2:1]=[C:2]([C:5]1[N:6]([CH2:16][O:17][CH3:18])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH2:3][CH3:4].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30](=[O:31])[CH:29]3[CH:28]([CH2:1][CH:2]([CH2:3][CH3:4])[C:5]4[N:6]([CH2:16][O:17][CH3:18])[C:7]5[C:12]([C:13]=43)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=5)[C:27]2=[O:32])=[CH:24][CH:25]=1
Reactant: C=C(CC)c1cc2cc(OC)ccc2n1COC
Reactant: Cc1ccc(N2C(=O)C=CC2=O)cc1
Solvent: Cc1ccccc1C
Product: CCC1CC2C(=O)N(c3ccc(C)cc3)C(=O)C2c2c1n(COC)c1ccc(OC)cc21
Yield: 49.9 %

Procedure:
5 ml of xylene was added to a mixture of 580 mg of 2-(1-buten-2-yl)-5-methoxy-1-methoxymethylindole and 880 mg of N-(4-methylphenyl)maleimide. The mixture was refluxed for 1.5 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate=5/1 to 2/1) to obtain 510 mg (yield: 50%) of N-(4-methylphenyl)-1-ethyl-6-methoxy-9-methoxymethyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide as colorless crystals.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:20](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.199 mL, 0.398 mmol) was added to a solution of (3-chloro-5-fluoro-phenyl)acetic acid (50 mg, 0.265 mmol) in methanol (0.5 mL) and toluene (2 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH2:1]([N:8]([CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21])[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Reactant: O=Cc1ccc(F)cc1F
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 8A and 2,4-difluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.40-7.18 (m, 6H), 7.11 (m, 2H), 6.92 (m, 1H), 6.72 (m, 2H), 6.07 (s, 1H), 4.07 (s, 4H), 2.93 (s, 3H), 2.30 (s, 3H); MS(ESI+) m/z 417 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:17]3[C:21](=[O:22])[C@@H:20]([CH2:23][CH2:24][C:25](O)=O)[NH:19][C:18]3=[O:28])[CH:14]([CH3:16])C)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)N[C@H:36]([C:45]1NC(C2C=CC=CC=2F)=CN=1)[C@H:37]([C:39]1C=CC=C[CH:40]=1)C)(C)(C)C.IC1C=CC(C(=O)C)=CC=1.C(OC(N[C@H](C1C=CC(OCC(=O)N(C)C)=CC=1)C(O)=O)=O)(C)(C)C.ClN1C(=O)CCC1=O.C(OC(N[C@H](CC#C)C(O)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl[Si](C)(C)C>C(N(CC)CC)C.C(O)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:17]3[C:21](=[O:22])[C@@H:20]([CH2:23][C:24]#[CH:25])[NH:19][C:18]3=[O:28])[CH2:14][C:16]3[CH:40]=[CH:39][CH:37]=[CH:36][CH:45]=3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Agent: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(=O)c1ccc(I)cc1
Agent: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Solvent: CCN(CC)CC
Product: C#CC[C@H]1NC(=O)N([C@@H](Cc2ccccc2)c2ncc(-c3ccc(I)cc3)[nH]2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B, and C were omitted; (ii) commercially available 1-(4-iodo-phenyl)-ethanone was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 18-D; (iii) (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 18-E; (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 18-F was omitted; (v) (R)-2-tert-butoxycarbonylamino-pent-4-ynoic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 18-G; and (vi) in step 18-H, formic acid (neat) heated to 30° C. was used in place of trifluoroacetic acid and silylation with chlorotrimethylsilane and triethylamine was omitted. HR-MS: calcd for C23H19IN4O2 [M+H+] 511.0626. Found 511.0623.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:12][C@@H:13]([CH3:29])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(C(=O)O)cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 93 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-acetylthiazole-4-carboxylic acid (1.444 g, 8.44 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (2.0 g, 7.67 mmol). The product was purified by recrystallization from ethanol. Yield 93%. 1H-NMR (400 MHz; DMSO-d6): δ 1.20 (d, 3H), 2.70 (s, 3H), 4.37 (dd, 1H), 4.44 (dd, 1H), 4.48-4.56 (m, 1H), 6.96 (d, 1H), 7.87 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.04 (d, 1H), 8.48 (d, 1H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH:23]=[CH2:24])[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]C=C)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[OH:21][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][C@H:7]3[CH2:22][CH:23]=[CH:24][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:48])[C:44]([F:45])([F:46])[F:47])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCC=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Yield: 67 %

Procedure:
Benzylidenebis(tricyclohexyl-phosphine)-dichlororuthenium (98 mg, 0.11 mmol) was added to a solution of 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol (723 mg, 2.21 mmol) and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate (1.59 g, 4.43 mmol) in dichloromethane (20 ml), followed by heating under reflux for 20 hours under argon atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (eluent: hexane/ethyl acetate=4/1) to give ethyl 11-[17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-penta-fluoropentyl)-9-undecenoate (973 mg, Yield 67%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br>[OH-].[Na+]>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH:10]=1
Reactant: Cc1coc2cc(O)ccc12
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1coc2cc(OCCCBr)ccc12
Temperature: 80 °C
Yield: 169.6 %

Procedure:
To a solution of 3-methyl-1-benzofuran-6-ol (0.20 g, 1.35 mmol) in NaOH (6 M aqueous solution, 0.25 mL) was added 1,3-dibromopropane (0.48 mL, 0.46 mmol), and the mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to rt, and NaOH (6 M aqueous solution, 0.11 mL) was added. The reaction mixture was heated at 80° C. for 1 h, cooled to rt, and partitioned between CH2Cl2 and NaHCO3 (saturated aqueous solution). The organic layer was dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexane (v/v)=1:19) to give 210 mg (58%) of the title compound containing minor impurities. This material was used in next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 1H), 7.32 (s, 1H), 7.0 (s, 1H), 6.88 (dd, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 2.40-2.28 (m, 2H), 2.20 (s, 3H).