Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[NH4+].[Si]([O:10][C@H:11]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=1)[CH2:12][NH:13][C@H:14]([CH3:33])[CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([NH:25][CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:24])[CH:19]=[CH:20][CH:21]=1)(C(C)(C)C)(C)C>CO.O>[CH:26]1([NH:25][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][C@H:14]([NH:13][CH2:12][C@H:11]([OH:10])[C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([CH2:41][OH:42])[CH:35]=3)[CH3:33])[CH:17]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C[C@H](Cc1cccc(CC(=O)NC2CCCCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@H](Cc1cccc(CC(=O)NC2CCCCCC2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 40 °C
Yield: 73.6 %

Procedure:
Ammonium fluoride (98 mg, 2.64 mmol) was added in one portion to a stirred solution of 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cycloheptylacetamide (Preparation 1) (150 mg, 0.26 mmol) in methanol (3 ml) and water (1.5 ml) at room temperature. The reaction was heated at 40° C. for 18 hours and then allowed to cool to room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (30 ml) and water (20 ml), the organic layer was separated, washed with brine (10 ml), dried (magnesium sulfate) and the solvent removed in vacuo to yield a clear oil. This was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: ammonia (90:10:1 by volume) to furnish the title compound as a white foam (87 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([N:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1)=[O:26]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N2CCC3(CC2)Cc2ccccc2O3)cc(OC)c1OC

Procedure:
A stirred mixture of 5.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 15 g of sodium bicarbonate in 75 ml of chloroform is treated with a mixture of 8.8 g of 3,4,5-trimethoxybenzoyl chloride in 125 ml of chloroform according to the procedure of Example 7 to provide a tan solid. The solid is sequentially recrystallized from ethyl alcohol, chromatographed through a silica gel column with a 2% methyl alcohol in chloroform eluant and recrystallized from ethyl alcohol to give the product, 2,3-dihydro-1'-(3,4,5-trimethoxybenzoyl)spiro[benzofuran-2,4'-piperidine], mp 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35]COCCOC)=[CH:28][CH:27]=3)[CH:16]=[C:17]([O:19]COCCOC)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=3)[CH:16]=[C:17]([OH:19])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COCCOCOCCOc1ccc(-c2cc(OCOCCOC)cc(-c3ccc(OCCCO)c(F)c3)c2)cc1
Agent: Cl
Solvent: CO
Product: OCCCOc1ccc(-c2cc(O)cc(-c3ccc(OCCO)cc3)c2)cc1F
Temperature: 50 °C

Procedure:
2.20 g (4.15 mmol) 3-{3″-fluoro-5′-(2-methoxy-ethoxymethoxy)-4-[2-(2-methoxy-ethoxymethoxy)-ethoxy]-[1,1′;3′,1″]terphenyl-4″-yloxy}-propane-1-ol are dissolved in 25 ml methanol and after addition of 3 ml conc. hydrochloric acid heated overnight at 50° C. The solvent is removed in vacuo, the crude product is dissolved in MTB ether, washed with water and sat. aq. sodium chloride solution, and dried over sodium sulfate. The solvent is removed in vacuo and the crude product is crystallized from dichloromethane. 3″-Fluoro-4-(2-hydroxy-ethoxy)-4″-(3-hydroxy-propoxy)-[1,1′;3′,1″]terphenyl-5′-ol is obtained as colourless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].F[B-](F)(F)F.[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N+]3C(C4C=CC=CC=4)=CC(C4C=CC=CC=4)=CC=3C3C=CC=CC=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1>CC1C=CC=CC=1>[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1
Reactant: Oc1ccncc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)C[C@H]1OC
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCOc2ccncc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 2.36 parts of 4-pyridinol, 1.2 parts of a sodium hydride dispersion 50% and 18 parts of methylbenzene was stirred for 2 hours at room temperature. A solution of 7.1 parts of cis-1-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-2,4,6-triphenylpyridinium tetrafluoroborate in 9 parts of methylbenzene was added and stirring was continued first for 4 hours at reflux temperature and then overnight at room temperature. The whole was extracted five times with 100 parts of a hydrochloric acid solution 1N. The combined acid aqueous phases were treated with potassium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.23 parts (28.3%) of cis-4-amino-5-chloro-2-methoxy-N-[3methoxy-1-[2-(4-pyridinyloxy)ethyl]-4piperidinyl]benzamide; mp. 212.2° C. (compound 60).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:13][CH2:12][CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(SCCO)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A homogeneous mixture of 2-[(5-nitro-2-pyridinyl)thio]ethanol (7) (45 mg, 0.22 mmol), 4-chlorobenzoyl chloride (33 μL, 0.26 mmol) and pyridine (45 μL, 0.56 mmol) in anhydrous dichloromethane (1.5 mL) was stirred at room temperature for 48 h. The reaction mixture was quenched with 1N HCl and the organic phase was washed with saturated aqueous solution of NaHCO3, brine and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethyl 4-chlorobenzoate (8). LCMS: purity: 90%; MS (m/e): 340 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][C:31]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1ccccc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and phenyl-acetic acid to yield (3aR,4S,7aR)-methyl 4-(2-phenylacetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.221 min; LC-MS Method II
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1C(=O)OC
Temperature: 0 °C

Procedure:
Methyl salicylate (4.6 g, 30 mmol) was treated with ethyl 4-bromobutyrate (6.5 g, 33 mmol) followed by the addition of potassium carbonate (4.6 g, 33 mmol), potassium iodide (61 mg, 0.36 mmol) and acetone (75 mL). The mixture was heated at reflux for 16 hours, cooled and filtered to remove the solids. The solids were washed with additional acetone and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in ether (150 mL), cooled to 0° C., washed with 40 mL of 0.5 M sodium hydroxide, washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and the residue chromatographed on silica gel eluting with a gradient of hexane:EtOAc (10:1, 5:1 and 4:1) to provide the title compound. 1H NMR (CDCl3) δ 1.25 (t, J=7.12 Hz, 3H), 2.09-2.22 (m, 2H), 2.59 (t, J=7.29 Hz, 2H), 3.89 (s, 3H), 4.06-4.19 (m, 4H), 6.93-7.03 (m, J=8.14, 8.14 Hz, 2H), 7.40-7.48 (m, 1H), 7.78 (dd, J=7.63, 1.86 Hz, 1H); MS (M+H)+ m/z 267.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25]>C(#N)C.CN(C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[C:20]2[OH:25])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc2c(O)cccc12
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C(Nc1cccc2c(O)cccc12)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
22.4 g of 3-nitro-4-fluorobenzoyl chloride (0.12 mols) were added dropwise at 0° C. to a suspension of 19.1 g of 5-amino-1-naphthol (0.12 mols) in 120 ml of acetonitrile and 14.2 g of N,N-dimethylaniline. The mixture was further stirred until it reached room temperature, and then heated for 30 minutes at 50° C. The yellow deposit was suction filtered and washed with acetonitrile. The deposit was dissolved in tetrahydrofurane and stirred with charcoal, filtered and the product was precipitated from the filtrate with petrol 50/75. Yield: 25.8 g=66% of the theoretical yield; mp. 235°-238° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([O:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:11]3)=[CH:5][CH:4]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 110.0 mg (70%) of the title compound as an orange oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:26]2[CH:31]=[CH:30][C:29](Cl)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=4)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:26]2[CH:31]=[CH:30][C:29]([NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Cl)c([N+](=O)[O-])c3)CCC2c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(NCc5ccc(OC)cc5)c([N+](=O)[O-])c4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Yield: 67.3 %

Procedure:
The product from Example 28D (4.41 g, 8.57 mmol) was combined, neat, with p-methoxy benzylamine (8.93 mL, 68.6 mmol) and heated at 145° C. for 1 h. The mixture was diluted with dichloromethane and filtered. The filtrate was washed with 0.5 M HCl, then NaHCO3 soln, then brine, concentrated and purified by chromatography on silica gel with an 80 g column, eluting with 0-50% ethyl acetate/hexanes to give 4.13 g (67%) of an orange foamy solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]>CCCCCCC.C(O)(C)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[C:24]([F:27])([F:25])[F:26])(=[O:16])=[O:15])[CH2:11][C@H:10]2[O:28][CH3:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
Racemic (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 58) was subjected to chiral preparative HPLC on Chiralpak AD using heptane/isopropanol 75:25 as eluant. The title compound was eluated as the second peak. MS (EI): 495.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([F:11])[CH:4]=1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(F)c1
Yield: 100 %

Procedure:
To a solution of 4-bromo-3-fluoro-benzoic acid (5.0 g, 22.9 mmol) in MeOH (60 mL) was added thionyl chloride (10 mL), This mixture was heated for about 5 h at 80 degrees Celsius until the starting material had been consumed, and then evaporated in vacuo to give white solid product (5.3 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=2.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+].CO>[CH3:23][N:6]1[C:7]2[C:12](=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=2)[C:13](=[O:15])[CH:14]=[C:5]1[CH2:4][C:3]([OH:2])=[O:18]
Reactant: COC(=O)Cc1cc(=O)c2c(OC)cccc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2c1c(=O)cc(CC(=O)O)n2C

Procedure:
The starting material can be obtained by condensation of 3-amino-4-chloroanisole with acetonedicarboxylic acid dimethyl ester to give 4-oxo-5-methoxy-8-chloro-1,4-dihydro-quinoline-2-acetic acid methyl ester, hydrogenation on 5% Pd-on-charcoal in dioxan at 6 atmospheres and 60° to give 4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid methyl ester, reaction with dimethyl sulphate in sodium hydroxide solution to give 1-methyl-4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid, hydrogenation on PtO2 in methanol at 20° and normal pressure to give 1-methyl-4-oxo-5-methoxy-1,2,3,4-tetrahydroquinoline-2-acetic acid, reaction, via the chloride and the amide, to give the nitrile, ether splitting by means of BBr3 to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetonitrile, reaction with Raney nickel to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetaldehyde, condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydro-2-quinolyl)-ethylidene]-2-thiazolin-5-one, condensation with acetone dicarboxylic acid monomethyl ester-monoamide to give 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-6-methyl-1,11-dioxo-6-aza-naphthacene-2-carboxamide (mixture of stereoisomers), epimerization with pyridine to give 4-de-dimethylamino-4-thiobenzamido-6-methyl-12a-dehydroxy-6-aza-tetracycline and hydroxylation.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24](ON3C(=O)CCC3=O)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>O1CCOCC1.O>[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:1]=3)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1ccc(N)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
4-((9-Fluorenylmethyloxycarbonyl)amino)aniline is prepared from p-phenylenediamine (2.16 g, 0.02 mole) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (6.75 g, 0.02 mole) in dioxane-water (1:1). Purification is achieved by crystallization. This product is coupled to BOC-L-Glu-α-O-Benzyl using HOBT/DCC. After the usual work-up, the fully-protected amino acid derivative is dissolved in MeOH and treated with hydrogen gas at 1 atmosphere pressure in the presence of palladium-on-carbon catalyst until hydrogen consumption is complete (about 2 hours). Following the usual workup, the starting material:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]=O.[ClH:12]>O1CCCC1>[ClH:12].[CH3:10][NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1NC=O
Agent: Cl
Solvent: C1CCOC1
Product: CNc1c(C)cccc1C
Temperature: 25 °C

Procedure:
A suspension of 125.6 g. of 2,6-dimethylformanilide in 1100 ml. of dry tetrahydrofuran is cooled to 0° C. in ice-methanol. To this with constant stirring is added dropwise over a period of 3 hours 1125 ml. of 0.96 M BH3 in tetrahydrofuran. This is then allowed to warm gradually to room temperature and then heated slowly to reflux. Refluxing is maintained for 6 hours and then stirred at room temperature another 15 hours. The reaction mixture is then cooled in ice and acidified with 425 ml. of 6 N HCl. A white solid forms. The mixture is evaporated in vacuo and the water-solid slurry dissolved into 2 l. of water. The solution is made strongly alkaline (with cooling) with 50% NaOH and then extracted twice with ether (2 l.) The ether is then washed three times with 100 ml. portions of water and twice with 100 ml. portions of saturation sodium chloride solution. The ether is then dried over sodium sulfate, filtered, acidified with ethereal HCl while cooling. The white solid which forms is filtered, washed with ether and sucked dry. This is recrystallized from isopropanol methanol to give N,2,6-trimethylaniline hydrochloride (m.p. 255-257 dec.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CC2CCc3[nH]c(C(=O)O)cc32)cc1C

Procedure:
The title compound was synthesized from methyl 4-(3,4-dimethylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.050 g, 0.18 mmol) and lithium hydroxide (0.076 g, 1.8 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane) to afford the title compound: 27 mg, 56% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.07 (ddt, J=12.40, 8.55, 6.00, 6.00 Hz, 1H), 2.16-2.29 (m, 7H), 2.45-2.73 (m, 5H), 3.22 (quin, J=6.97 Hz, 1H), 6.30 (s, 1H), 6.84-6.92 (m, 1H), 6.95 (s, 1H), 7.01 (d, J=7.61 Hz, 1H); LCMS-MS (ESI−) 268.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 67 mg of 2-propyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 170 mg of 4-(3-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (56)).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C(OCC)C.[Pd]>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1C=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
25.7 Parts of a mixture of the isomers (cis and trans) of 2-(2,2-diphenylethylidenyl)-1-azabicyclo[2.2.2]octan-3-one, and 2-(2,2-diphenylethenyl)-1-azabicyclo[2.2.2]octan-3-one is dissolved in 1000 parts by volume of ethanol. Then 5 parts of 5% palladium-on-carbon is added and the mixture is hydrogenated using a Parr low-pressure hydrogenator, at room temperature and a pressure of 60-30 psi for 4 hours. After the hydrogenation is completed the catalyst is removed by filtration. The solution is then stripped in vacuum to give a solid. The solid is dissolved in 500 parts by volume of hot ethyl ether. The solution is filtered and then concentrated on a steam bath to a volume of about 150 parts by volume. The concentrated solution is cooled in an ice-bath to afford a precipitate which is filtered off from the solvent, washed with cold ethyl ether and dried in vacuo to provide a white solid. This solid is recrystallized from ethyl ether to afford 2-(2,2-diphenylethyl)-1-azabicyclo[ 2.2.2]octan-3-one melting at 103°-107° C. This compound is represented by the following structural formula ##STR3##