Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]([C:33]1[CH:34]=[C:35]2[C:60](=[CH:61][CH:62]=1)[C:39]1[NH:40][C:41]([C@@H:43]4[CH2:47][C@H:46](C)[CH2:45][N:44]4[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[N:42][C:38]=1C=C2)=[CH:27][CH:26]=3)=[O:11])=[O:7])(C)(C)C.[F:69][CH:70]([F:127])[O:71]C1C=C(C2NC([C@@H]3CCCN3C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=2)C=CC=1C1C=C2C(=CC=1)C1NC([C@@H]3C[C@H](COC)CN3C(OC(C)(C)C)=O)=NC=1C=C2.C(OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O)(C)(C)C.COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:5][C:6]([NH:8][C@H:9]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]([C:33]1[CH:62]=[CH:61][C:60]([C:39]2[NH:40][C:41]([C@@H:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:49](=[O:59])[C@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:52])[CH3:53])=[N:42][CH:38]=2)=[CH:35][C:34]=1[O:71][CH:70]([F:127])[F:69])=[CH:27][CH:26]=3)=[O:11])=[O:7]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5OC(F)F)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)C(C)C)[nH]6)cc5OC(F)F)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1

Procedure:
Methyl (R)-1-((S)-2-(5-(4-(2-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was prepared according to the method employed in the synthesis of methyl (S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (2S,4S)-tert-butyl 2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate with (2S,4S)-tert-butyl 2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate and (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid. MS (ESI) m/z 907 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:22]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 64.3 %

Procedure:
Methyl 2-{[4-(3-hydroxypropyl)phenoxy]methyl}benzoate (0.50 g, 1.66 mmol) and 4-(benzyloxy)phenol (0.33 g, 1.66 mmol) was added to a dry round bottomed flask and fitted with septa. Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. (Tributylphosphoranylidene)acetonitrile (0.80 g, 3.33 mmol) was added dropwise and the reaction was performed in a single node microwave oven. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.515 gram of methyl 2-[(4-{3-[4-(benzyloxy)phenoxy]-propyl}phenoxy)methyl]benzoate (yield 64.1%).
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].I[CH3:17]>C(OCC)C.[Ag-]=O>[CH3:17][O:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)C(C)(C)c1ccccc1
Reactant: CI
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC(=O)C(OC)C(C)(C)c1ccccc1
Temperature: 40 °C
Reaction time: 26 h

Procedure:
To a solution of methyl 2-hydroxy-3-methyl-3-phenylbutanoate (0.50 g, 2.4 mmol, from Reference Example 37) in diethyl ether (11 mL) is added silver (I) oxide (4.3 g) and iodomethane (8.7 mL). The reaction mixture is stirred in a 40° C. oil bath under nitrogen atmosphere for 26 hours. The reaction mixture is combined with that from a previous run conducted under the same conditions and filtered through a plug of diatomaceous earth. The filtrate is concentrated under reduced pressure and then purified by flash chromatography (silica gel, hexanes/ethyl acetate) to furnish 0.52 g of a clear, colorless liquid (68% combined yield). MS (ES+): (M+H)=222.9
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1.O>CS(C)=O>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C@@H:19]2[CH2:4][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cn(C)c2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
To a suspension of sodium hydride (ca 60%, 21 mg, 0.52 mmol) in DMSO (1 mL) was added trimethylsulfoxonium iodide (115 mg, 0.52 mmol), and the mixture was stirred at room temperature for 20 minutes. Then, ethyl (E)-3-(1-methyl-1H-indol-3-yl)acrylate (Synlett, (9), 1319-1322 (2006)) (100 mg, 0.44 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 20 hours. After cooling to room temperature, the mixture was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (7:1) to give 23 mg (21% yield) of the title compound as a pale yellow oil:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Fc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: Fc1ccccc1CSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-fluorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 151°-153° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[N:12]([Si](C)(C)C)=[N+:13]=[N-:14].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:14][N:13]=[N:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccc(Cl)cc1F
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A stirred solution of 17.1 grams (0.10 mole) of 4-chloro-2-fluorophenyl isocyanate and 20.0 grams (0.17 mole) of azidotrimethylsilane was heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature and 60 ml of toluene and 100 ml of water were added. The mixture was allowed to stand for two hours and the resultant solid collected by filtration. The filter cake was washed with petroleum ether to yield 14.5 grams of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one; m.p. 185°-187° C. The reaction was repeated several times.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2
Reactant: [H][H]
Reactant: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-hexyl-1H-indole.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][CH:2]=[CH2:3])[CH3:9])[CH3:6]
Reactant: C=CCO
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: C=CCOC(C)OCC
Reaction time: 3 h

Procedure:
Allyl alcohol (46.8 ml. 40 g., 0.69 mol) and ethyl vinyl ether (98.8 ml., 74.5 g., 1.033 mols) were stirred together at -12°. dl-Camphorsulfonic acid (150 mg.) was added acid and stirring continued for 3 hours at that temperature. The mixture was then washed 1×100 ml. saturated NaHCO3, 1×100 ml. brine, dried and stripped to yield title product as an oil (100 ml., essentially quantitative yield). 1H-nmr: 1.14 (t, 3H), 1.29 (d, 3H), 3.56 (dp, 2H), 4.06 (m, 2H), 4.75 (q, 1H), 5.26 (m, 2H), 5.99 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([N:20]3[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Reactant: NC(=O)C1CCNCC1
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
A mixture of 10 g (35 mmol) of 4-chloro-2-(4-chlorophenyl)-6-methylquinoline, 8.9 g (70 mmol) of isonipecotamide, and 20 g of phenol was stirred and heated in an oil bath at 165°-170° for 3.5 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 11.9 g of crude product. Recrystallization from pyridine gave the named compound as off-white prisms, mp 261°-265° dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}phenyl)carbonyl]amino}propanoate (320 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (213 mg, 71%) as a pale-brown solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[N:5][CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[N:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (530 mg, 1.67 mmol) in dry DMF (5.6 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 348 mg, 1.84 mmol), HATU (953 mg, 2.51 mmol) and triethylamine (699 μl, 5.01 mmol) and then stirred at room temperature for 17 hours. The reaction was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The organics were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=C(F)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([F:39])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)C2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCC3(CC3N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A 346 mg (1.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-b) was dissolved in 30 ml of ethanol, and the solution was mixed with 350 mg of 10% palladium-carbon and subjected to 4 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 10 ml of acetonitrile, and the suspension was mixed with 210 mg (0.67 mmol) of 5-amino-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.93 ml (6.67 mmol) of triethylamine, and heated under reflux for 18 hours. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 30 minutes, adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was recrystallized from ethanol-ether to yield 198 mg (78%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[NH2:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[Cl:39][CH2:40][C:41](=N)OCC.C([O-])(O)=O.[Na+]>ClCCCl>[Si:1]([O:8][CH2:9][C@@H:10]([N:26]1[C:27]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:30]=[CH:29][C:28]=2[N:37]=[C:41]1[CH2:40][Cl:39])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 81.2 %

Procedure:
N4-[(1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]quinoline-3,4-diamine (23.46 g, 43.6 mmol) was dissolved in 400 mL of dry 1,2-dichloroethane and the yellow solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (13.8 g, 87.2 mmol) was then added and the reaction mixture was heated to 70° C. overnight. The reaction mixture was then cooled and treated with 300 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed sequentially with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10-60% ethyl acetate/hexanes) gave 1-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (21.11 g) as a brown foam.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[NH2:13][CH:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16]>>[OH:16][CH2:15][CH:14]([NH:13][C:1]([C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:12])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CC(C)CC(N)CO
Product: CC(C)CC(CO)NC(=O)c1ccc2c(c1)OCO2

Procedure:
N-(1-hydroxy-4-methylpentan-2-yl)benzo[d][1,3]dioxole-5-carboxamide was prepared in a similar manner to example 4 from piperonylic acid and 2-amino-4-methyl-pentan-1-ol.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:7]=[C:8](Br)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[CH2:23]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CCOCC.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.[Cu]I>[CH2:23]([C:28]1[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([O:5][Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:1]([CH3:3])[CH3:2])[CH:7]=2)=[CH:32][CH:33]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCc1ccc(C#Cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc3ccccc23)cc1
Yield: 33.1 %

Procedure:
A solution of 3-triisopropylsilyoxy-1-bromonaphthalene (2.32 g, 6.1 mmol), (4-pentylphenyl)acetylene (1.58 g, 9.2 mmol), Pd(PPh3)2Cl2 (129 mg, 3 mol %), PPh3 (240 mg, 15 mol %) and CuI (88 mg, 7.5 mol %) in Et3N (20 mL) under N2 was heated at reflux for 4 h. The resulting mixture was cooled, diluted with Et2O, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (0.95 g, 33%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 30.3 %

Procedure:
A mixture of 3.30 g (0.010 mole) of 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 2.006 g (0.012 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.400 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C1COCC1.N1CCNCC1>C(N(CC)CC)C>[CH3:19][CH:20]1[NH:21][CH:22]([CH3:26])[CH2:23][N:24]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:25]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CC(C)NC(C)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 2,6-cis-dimethylpiperazine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperazine derivative. The reaction mixture was evaporated to an oil and partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to a colorless solid (79 mg, 85%). 1H NMR (CDCl3) 1.03 (d, J=4.8, 6 H), 1.72-2.20 (m, 1H), 2.29 (s, 3H), 2.58 (br, 1H), 2.78-2.90 (m, 2H), 4.25 (br, 2H), 7.24-7.26 (m, 1H), 7.37-7.39 (m, 1H). 13C NMR 7.9, 19.4, ˜50 (br obsc), 51.3, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2, 140.2, 155.1 (q, J=40), 157.9, 162.4. 19F NMR −63.2. LC/MS 4.43 min, [M+1]+374.