Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5].[C:33]([O:37][C:38]([N:40]([C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[O:54][CH2:55][CH:56]1[CH2:58][CH2:57]1)C(O)=O)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl.CN([CH:66]=[O:67])C>CN(C1C=CN=CC=1)C.Cl>[C:33]([O:37][C:38]([N:40]([C:45]1[CH:46]=[CH:47][C:51]([C:66]([NH:2][CH2:3][C:4]([O:6][C@H:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:19]=2)[CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=2[Cl:17])=[O:5])=[O:67])=[CH:52][C:53]=1[O:54][CH2:55][CH:56]1[CH2:57][CH2:58]1)[S:41]([CH3:44])(=[O:42])=[O:43])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(c1cc(C(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
((S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride) (103 mg; 0.2 mmol) was dissolved in DMF (1.5 ml), then 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)benzoic acid (80 mg, 0.2 mmol), (for a reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety), EDC (80 mg, 0.42 mmol), and DMAP (60 mg, 0.49 mmol) were added. The reaction was stirred at RT overnight, then was diluted with HCl 1M and extracted with EtOAc. The organic phase was washed with HCl 1M and with K2CO3 sat, dried over Na2SO4 and evaporated under vacuum to give 180 mg of the desired product (Yield: quantitative).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:24][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[C:21]([Cl:23])=[CH:22][C:14]=2[CH2:13]1.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]21[CH2:53][C:45]1[CH:46]=[N:47][C:48]([C:50](O)=[O:51])=[CH:49][C:44]=1[CH2:43]2.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:21]1[C:20]2[NH:19][N:18]=[CH:17][C:16]=2[C:15]2[CH2:24][N:25]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:26](=[O:27])[C@H:12]([NH:11][C:50]([C:48]3[N:47]=[CH:46][C:45]4[CH2:53][C:35]5([CH2:43][C:44]=4[CH:49]=3)[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]5=[O:33])=[O:51])[CH2:13][C:14]=2[CH:22]=1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C(O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (7R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one bis-methanesulfonate (16 mg, 0.030 mmol, described in Example 7, Step B), (±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (8.6 mg, 0.030 mmol, described in Intermediate 5), N,N-diisopropylethylamine (20 mg, 27 uL, 0.15 mmol), HOBT (5.6 mg, 0.037 mmol), and EDC (7.0 mg, 0.037 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were concentrated in vacuo to provide the title compound. MS: m/z=596.
Reaction SMILES: CS([CH2:5][CH2:6][NH:7][C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:10]([O:12][CH3:13])=[O:11])(=O)=O.ClCCl.S([O-])(=O)(=O)C.[Br-:27].[Li+]>O>[Br:27][CH2:5][CH2:6][NH:7][C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=C(CC(=O)OC)NCCS(C)(=O)=O
Reactant: [Br-]
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=C(CC(=O)OC)NCCBr
Temperature: 35 °C
Reaction time: 19 h
Yield: 86.7 %

Procedure:
Dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate (156.3 g, 529 mmol) was added to a 2 L three-neck flask, which was fitted with a mechanical stirrer, thermometer, and reflux condenser. Dichloromethane (750 mL) was added and stirred until the mesylate had completely dissolved, anhydrous lithium bromide (69.0 g, 794 mmol) was added, and the mixture stirred at 35° C. for 19 hours. The mixture was cooled to 0° C. and water (250 mL) added, then stirred for 5 minutes and the phases separated. The organic phase was washed with water (3×250 mL) and brine (150 mL), and dried over anhydrous potassium carbonate for 15 minutes. Rotary evaporation of the solvent under reduced pressure (50° C.) gave 128.4 g of crude dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a yellow oil, which quickly solidified to a yellow solid. The crude material was purified by extraction into boiling hexane (5×750 mL) and recrystallization from hexane, and the pot residues extracted and recrystallized, to give a total of 90.8 g (61.2% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as white needles. An NMR spectrum in CDCl3 indicated an Z/E isomer ratio of 19:1, and remeasurement of the CDCl3 solution after three days indicated an Z/E ratio of 4:1. The two isomers were not separated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN(C)[CH:56]=[O:57].C[CH2:60][O:61]CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:60]([O:57][CH3:56])=[O:61])=[CH:12][CH:11]=1)[CH3:9])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A mixture of tert-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate (step 3, 14.73 g, 49.1 mmol), 1,3-bis(diphenylphosphino)-propane (2.03 g, 4.91 mmol), palladium (II) acetate (1.10 g, 4.91 mmol), triethylamine (20.5 mL, 147 mmol), N,N-dimethylforamide (120 mL) and methanol (180 mL) was stirred at 80° C. for 16 h under carbon monoxide atmosphere. After cooling to room temperature, the mixture was diluted with ether (800 mL) and washed with water (500 mL×3). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (5:1) to afford 12.83 g (94%) of the title compound as white solids:
Reaction SMILES: [C:1]([N:8](C)[C@H:9](C=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C([Cl:19])(=O)C.[CH:20](OC)([O:23][CH3:24])[O:21][CH3:22]>CO>[ClH:19].[CH3:22][O:21][CH:20]([O:23][CH3:24])[C@@H:9]([NH:8][CH3:1])[CH:10]([CH3:12])[CH3:11]
Reactant: COC(OC)OC
Reactant: CC(=O)Cl
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Solvent: CO
Product: CN[C@@H](C(C)C)C(OC)OC
Product: Cl
Temperature: 15 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
5.0 g Crude Boc-N-methyl-valinal (23.2 mmol) were dissolved in 40 ml methanol and cooled to ˜15° C. A solution of 3.3 ml (46.4 mmol) acetyl chloride in 10 ml methanol was added all at once and the yellowish solution was stirred at RT for 1 h (gas evolution). 22.2 g Trimethyl orthoformate (209 mmol) were now added and the reaction mixture was stirred at RT over night (18 h). The solvent and the excess of the orthoester were removed by rotary evaporation (40° C./≧10 mbar) and the resulting beige, crystalline residue (4.6 g) was dissolved in ca. 45 ml isopropyl acetate at ˜70° C. After cooling to RT and crystallization at −20° C. for 17 h the crystal suspension was filtered and dried (50° C./10 mbar/16 h) affording 3.2 g (69%) product as greenish needles, [α]D=40.3 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccncc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 16 h
Yield: 41.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.074 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.22 mmol, 0.22 mL) and 4-methoxybenzene carboxaldehyde (1.05 eq, 0.077 mmol, 0.0096 mL). After 16 h, filtration of the precipitate and washing with ethanol (1 mL) and cold water (1 mL) gave the product (15 mg, 42%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.37 (d, J=6.7 Hz, 3H, CHCH3), 2.56-2.65 (2 m, 4H, piperazine N(CH2)2), 3.58 (q, J=6.9 Hz, 1H, CHCH3), 3.66 (br s, 4H, piperazine N(CH2)2), 3.85 (s, 3H, OCH3), 7.11 (d, J=8.8 Hz, 2H, methoxyphenyl), 7.40 (d, J=5.4 Hz, 2H, pyridine H-3 & H-5), 8.14 (d, J=8.5 Hz, 2H, methoxyphenyl), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.55 (d, J=5.4 Hz, 2H, pyridine H-2 & H-6), 13.40 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[F:23][C:24]([F:29])([F:28])[C:25]([CH3:27])=[O:26]>O1CCCC1>[F:23][C:24]([F:29])([F:28])[C:25]([OH:26])([CH3:27])[C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
To a cooled (-78° C.) solution of 4-phenylsulfonylphenylethyne (66 mg, 0.27 mmol) in freshly distilled tetrahydrofuran (2.5 mL) was added n-BuLi (109 mL, 2.5M solution in hexanes, 0.27 mmol). The solution was stirred for 10 minutes at -78° C. at which time 1,1,1-trifluoroacetone (272 mL, 1.0M solution in tetrahydrofuran, 0.27 mmol) was added. The reaction mixture was kept at -78° C. for five minutes before quenching with 2N HCl . Diethyl ether was added, and the aqueous layer extracted further with diethyl ether. The combined organic layers were dried, evaporated and the product purified by chromatography, with ethyl acetate:hexanes as eluent (1:4) to yield the title butyne as a white solid (72 mg, 75%); mp 94.8°-95.3° C.; 250 MHz NMR (CDCl3): 1.72 (s,3, CH3), 3.08 (s,1, OH), 7.48-7.60 (m,5, Ar), 7.87-7.94 (m,4, Ar); MS: m/z=355(M+ 1). Analysis for C17H13F3O3S: Calculated: C, 57.62; H, 3.70; Found: C, 57.46; H, 3.65.
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[N+:2]=[N-:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[C:4]12([N:1]3[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:21][N:3]=[N:2]3)[CH2:5][CH:6]3[CH2:12][CH:10]([CH2:9][CH:8]([CH2:7]3)[CH2:13]1)[CH2:11]2
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NC12CC3CC(CC(C3)C1)C2
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnnn2C23CC4CC(CC(C4)C2)C3)cc1
Yield: 52 %

Procedure:
1-Azidoadamantane (177 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 12 hours. Product obtained as off-white powder in 52% yield (145 mg). ESI-MS: m/z 280, [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: COc1cccc(OCCBr)c1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(OCCn2cc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (220 mg, 1.90 mmol) in MeCN (9.5 mL), 1-(2-bromoethoxy)-3-methoxybenzene (495 mg, 2.14 mmol) dissolved in MeCN (1.5 mL) and Cs2CO3 (697 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1-(2-(3-methoxyphenoxy)ethyl)-4-nitro-1H-pyrazole which was used in the next step without further purification. LC-MS conditions A: tR=0.85 min, [M+H]+=no ionization.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:35])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:21]([CH2:20][CH2:19][C:18]([OH:35])=[O:17])[CH:26]=1
Reactant: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccc(Cl)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 70.9 %

Procedure:
Using the procedure of example 4,5-chloro-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester, a pale-yellow oil, was prepared in quantitative yield starting from 0.62 g (3 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 1.21 g (3.33 mmol) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester. Saponification using the procedure of example 4 afforded 1.01 g (71%) of 5-chloro-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as a colorless solid, mp 101°-103° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.[Na].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O.CCCCCC>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
NaH (1.42 g of 60% in oil, 0.036 mol) was washed 2×5 ml hexane and then suspended in tetrahydrofuran (20 ml). 4-Hydroxyphenethyl alcohol (5.0 g, 0.036 mol) was added portionwise and the mixture stirred for 20 minutes to assure complete conversion to the sodium salt. Benzyl bromide (4.2 ml, 1 equivalent) was added and the resulting mixture refluxed for 4 hours, then poured into 50 ml H2O and extracted 3×50 ml ether. The organic layers were combined, extracted 2×20 ml 1N NaOH and then 2×20 ml H2O, dried (MgSO4), stripped, and the solid residue recrystallized from ethyl acetate and cyclohexane to yield title product 4.4 g.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)nccc23)c1
Yield: 16.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-6, 100 mg, 0.329 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 133 mg, 0.493 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (129 mg, 1.00 mmol) in CH2Cl2 (5 mL) to afford 31 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.22 (br t, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.98 (d, J=5.7 Hz, 1H), 7.82-7.67 (m, 6H), 7.55 (m, 2H), 7.39 (d, 1H), 4.34-4.32 (d, J=5.7 Hz, 2H), 1.14 (s, 9H); MS [M+H]+: 556.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:6]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:14].CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][N:5]2[CH:6]=[CH:2][CH:3]=[C:4]2[C:7]([O:9][CH3:10])=[O:8])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(OC)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of methyl 4-bromo-1H-pyrrole-2-carboxylate (1 g, 4.9 mmol) and 2-bromo-1-(4-methoxyphenyl)ethanone (1.23 g, 5.3 mmol) in DMF (30 mL) was added potassium tert-butoxide (0.60 g, 5.4 mmol) portionwise at −15° C. The mixture was stirred at that temperate for 15 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous HCl (1M) and then extracted with EtOAc (3×100 mL). The organic layers were washed with brine, water and then concentrated in vacuo to give a liquid. This was azeotroped with toluene to give a residue corresponding to methyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate. ESI-MI m/z [M+H]+ 353.8. The crude was used in the next step without purification
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]C(O)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CC(=O)O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CC(O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.75 h

Procedure:
To a solution of 1J (˜0.05 M in THF) at −78° C. was added dropwise MeMgBr (3.0M in Et2O, 3 equiv). The reaction was stirred at −78° C. for 1.5-2 h (quench small aliquot in 10% MeOH/DCM, spot TLC-silica gel, 30% EtOAc/Hex-stain with 5% HCl/MeOH, heat and then ninhydrin, heat). Quench reaction by addition of HOAc (3 equiv) at −78° C. Warm to rt, dilute with EtOAc and wash with a 1:1 mixture of saturated aq. NaHCO3 and brine. Back extract aqueous layer. Combine organic extracts, dry over MgSO4, filter and concentrate. Purification by flash chromatography (silica gel, step gradient 0-10-20% EtOAc in hexane) provided the title compound.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=O)=O)C.S(=O)(=O)(O)O.O>C(O)C>[CH3:1][N:2]1[C:7](=[O:6])[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[CH:14]=[N:3]1
Reactant: CNN
Reactant: CCOC(=O)c1cc[nH]c1C=O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cn1ncc2[nH]ccc2c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of methylhydrazine (4.84 g) and 3-ethoxycarbonyl-2-formylpyrrole (3.34 g) in ethanol (30 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was further refluxed for 19 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=19:1) to provide the title compound as white powder (1.81 g; yield 61%). 1 H-NMR (DMSO-d6) δ: 3.68(3H,s), 6.65(1H,d,J=2.8Hz), 7.42(1H,t,J=2.8Hz), 8.17(1H,s), 12.02(1H,m).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[C:20](=O)(O)[O-].[Na+].IC>CN(C)C=O>[CH3:3][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
To a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodomethane (16 g, 113 mmole). The mixture is heated at 40° under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2 ×100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil.
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].CS(C)=O.[CH:15]#[CH:16].[CH2:17](OCC)[CH3:18]>O1CCOCC1>[CH:15]([N:7]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:18]=[CH:17]1)=[CH2:16]
Reactant: ON=C1CCCCC1
Reactant: C#C
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: C=Cn1ccc2c1CCCC2
Yield: 91.6 %

Procedure:
5 g of cyclohexanone oxime, 1 g of potassium hydroxide, 50 ml of dimethylsulfoxide and 50 ml of dioxane are heated for a period of one hour at the temperature of 140° C in the presence of a 5-fold excess of acetylene (with respect to the stoichiometric amount thereof). After extraction with diethyl ether and distillation 5.4 g (yield is 91.6%) of 1-vinyl-4,5,6,7-tetrahydroindole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]4NC(=O)O[C:18]=4[CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:29][O:30]C1C=CC(N)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]([O:30][CH3:29])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Product: COc1ccc(NCC(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233) and 4-methoxy-aniline according to the method described in Example 206. Melting Point: 127-130° C. (diethylether)