Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:21][CH:20]2[CH:16]([CH2:17][NH:18][CH2:19]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(O)CCC>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]2[CH:20]([CH2:19][N:18]([C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:17]2)[CH2:21]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3nccs3)CC2C1
Yield: 25.5 %

Procedure:
A solution of 541 μl (6.0 mmol) 2-bromothiazole and 1.27 g (6.0 mmol) hexahydro-pyrrolo[3,4-c]pyrrol-2-carboxylic acid tert-butyl-ester in n-butanol (10 ml) was heated for 2 h under reflux. Subsequently, the solvent was removed in vacuo and the residue taken up by chloroform. This solution was washed with water and brine in turn, dried over MgSO4, filtered and concentrated in vacuo. Column chromatography was carried out on the residue (SiO2, DCM/EtOH 10:1), yielding 450 mg (1.53 mmol, 25%) 5-thiazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-carboxylic acid tert-butyl-ester.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.C1(OP([CH:28]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=2)NC2C=CC=CC=2)(=O)OC2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=[O:44].[Cs+].[Cs+].Cl>C1COCC1.CC(O)C.C(OC)(C)(C)C>[CH3:42][C:38]1[N:37]=[C:36]([C:28](=[O:44])[CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[CH:2][N:1]=3)[CH:9]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C(Nc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)n1
Reactant: O=Cc1ccc2ncnn2c1
Agent: Cl
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Cc2ccc3ncnn3c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde (3 g, 20 mmol; see subpart (a) above) and [(6-methyl-pyridin-2-yl)-phenylamino-methyl]-phosphonic acid diphenyl ester (8.8 g, 20 mmol; prepared from 6-methyl-pyridine-2-carboxaldehyde (Aldrich-Sigma, St. Louis, Mo.) according to Tetrahedron Lett. 39:1717-1720 (1998)) in a mixture of THF (40 mL) and iPrOH (10 mL) was added Cs2CO3 (8.6 g, 26 mmol) and the mixture was stirred at room temperature for overnight. A solution of 3N HCl (30 mL) was added dropwise to the above mixture and stirred for 1 hour. It was then diluted with MTBE (methyl t-butyl ether) and extracted with 1N HCl twice. The aqueous extracts were neutralized with ca. 50% KOH until pH 7-8 was reached and precipitates formed. The precipitates were collected, washed with water, and dried to yield 1-(6-methyl-pyridin-2-yl)-2-[1,2,4]triazolo[1,5-a]pyridin-6-yl-ethanone as an offwhite solid (2.9 g). The filtrates were extracted with EtOAc and dried over MgSO4 and concentrated. The residue was recrystalized with iPrOH/H2O to yield more desired product (0.6 g). ESP+, m/e 253. 1H NMR (CDCl3, 300 MHz), δ 8.6 (s, 1H), 8.29 (s, 1H), 7.87 (d, 1H), 7.72 (t, 1H),7.70 (d, 1H), 7.53 (dd, 1H), 7.36 (d, 1H), 4.61 (s, 2H), 2.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCC1(O)CCOCC1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCOCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (16.6 g, 79.0 mmol) in dichloromethane (250 mL) and triethylamine (14.3 mL, 102.7 mmol) was cooled to 4° C. A solution of 4-aminomethyltetrahydropyran-4-ol (11.4 g, 86.9 mmol) in dichloromethane (70 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to stir at ambient temperature over the weekend and then it was concentrated under reduced pressure. The residue was stirred with water (300 mL). The resulting solid was isolated by filtration, rinsed with water, and dried in a vacuum oven at 50° C. for 4 hours to provide 22.53 g of 4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[C:2]#[CH:3].[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)=[O:23])[CH3:20].[CH2:30]=O>O1CCOCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:25]1)=[O:23])[CH3:20]
Reactant: C=O
Reactant: C#CCN1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CCCN(CC#CCN2c3ccccc3CCc3ccccc32)C1
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution containing 5-propargyl-10,11-dihydro-5H-dibenzo[b,f]azepine (2.45 g, 10.5 mmol, prepared similarly as described in U.S. Pat. No. 3,354,178 (1967)), (R)-3-piperidinecarboxylic acid ethyl ester (1.7 g, 10.8 mmol), paraformaldehyde (0.65 g) and a trace of cuprous chloride in dioxane (25 ml) was heated at reflux temperature for 5 h and left standing overnight. The mixture was filtered and the solvent evaporated. The remaining oil was purified by column chromatography on silica gel (40 g) using chloroform as eluent, affording 3.5 g (83%) of (R)-1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-butyn-1-yl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O=C(Cl)[O:36][C:37](Cl)(Cl)Cl.[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][NH:47][CH3:48]>C(OCC)C>[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][N:47]([CH3:48])[C:37](=[O:36])[O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Reactant: CNCCCN(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)N(C)CCCN(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (0.5 g, 1.1 mmol) in anhydrous diethyl ether (10 mL) was added slowly a solution of diphosgene (0.2 mL, 1.8 mmol) in anhydrous diethyl ether cooled to approximately −15° C. The solution was stirred for 1 hour then N,N,N′-trimethyl-1,3-propanediamine (1.3 mL, 8.7 mmol) was added at −15° C. The solution was warmed to room temperature, stirred for 1 hour, and then filtered to remove the ammonium salts and urea. The diethyl ether filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 3-(dimethylamino)propyl(methyl)carbamate 23 as a colorless oil (0.15 g, 23%), 1H NMR (400 MHz, CDCl3) δ 5.41-5.29 (m, 6H), 4.85-4.77 (m, 1H), 3.35-3.21 (m, 2H), 2.93-2.81 (m, 3H), 2.31-2.17 (m, 8H), 2.08-1.92 (m, 12H), 1.75-1.64 (m, 2H), 1.64-1.15 (m, 31H), 0.92-0.85 (m, 9H). Rf 0.45 (10% MeOH—CH2Cl2).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29]([OH:31])=O)=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH2:63].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1([NH:20][C:21]([CH:23]2[CH2:27][CH:26]([OH:28])[CH2:25][CH:24]2[C:29](=[O:31])[N:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH2:63])[CH3:56])=[O:22])[CH2:17][CH:16]1[CH:18]=[CH2:19])=[O:14])[CH3:11]
Reactant: C=CCCCCNC
Reactant: C=CC1CC1(NC(=O)C1CC(O)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
The crude compound 10b (5.5 mol) was dissolved in DCM (50 mL) and DMF (14 mL) followed by addition of HATU (2.09 g, 5.5 mmol), N-methyl-N-hex-5-enylamin (678 mg, 6.0 mmol) and DIPEA (3.08 mL, 17.5 mmol) at room temperature. The reaction was stirred at ambient temperature for 1 h. LC/MS analysis showed complete conversion of the starting materials and the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (100 mL) and the organic phase washed with 0.1 M HCl (aq), K2CO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo gave an oil which was purified by flash chromatography (Silica, EtOAc:MeOH) to afford the title compound (1.65 g, 74%). TLC (Silica): MeOH:EtOAc 5:95, Rf=0.5; LC/MS >95%, m/z (ESI+)=407 (MH+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=3)[NH2:32])[CH2:23][CH2:22]2)[N:12]=1.CS([O:40][CH2:41][CH2:42][C:43]1C=CC=C(N2CCCC2=O)[CH:44]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[C:31]([N:32]4[CH2:44][CH2:43][CH2:42][C:41]4=[O:40])[CH:33]=[CH:34][CH:35]=3)[CH2:25][CH2:26]2)[N:12]=1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2=O)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCCC5=O)c4)CC3)cccc2n1
Temperature: 100 °C
Yield: 77 %

Procedure:
N,N-Diisopropylethylamine (0.23 mL) was added to a solution of 2-methyl-5-(1-piperazinyl)quinoline (D3) (0.05 g) and 2-[3-(2-oxo-1-pyrrolidinyl)phenyl]ethyl methanesulfonate (0.071 g) in dimethylformamide (1 mL) and the resulting mixture was heated to 100° C. for 18 hours, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), a mixture of water and brine (1:1, 2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with methanol-ethyl acetate (90:10) affording the title compound in 77% yield (0.07 g).
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3]C=1.[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:27]1[CH:32]=[CH:31][C:30](S(Cl)(=O)=O)=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:24])[CH3:25])[N:22]([C:30]1[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=1)[S:7]([CH2:4][CH3:3])(=[O:9])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccncc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)N(c1ccncc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 1 h

Procedure:
To 1 gm of valine benzyl ester p-toluene-sulfonic acid salt in 40 ml of CH2Cl2 at 0° C. was added 1.12 gm of 4-pyridylsulfonyl chloride (U.S. Pat. No. 431,504 (1982)) and 1.9 ml of triethylamino. After 1 hour, the solution was washed with water and extracted with CH2Cl2 (2×100 ml), dried and concentrated. Silica gel column chromotography provided 4-pyridyl-ethanesulfonyl-valine benzyl ester which was treated with 10% Pd/C in methanol under hydrogen atmosphere to provide the desired product in 85% overall yeild.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13]O.[Cl:15]CCl.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][Cl:15]
Reactant: ClCCl
Reactant: Cn1ncc(Cl)c(NCCCO)c1=O
Solvent: O=S(Cl)Cl
Product: Cn1ncc(Cl)c(NCCCCl)c1=O
Reaction time: 3 h
Yield: 73.2 %

Procedure:
0.48 g (2.2 mmoles) of 5-chloro-4-[N-(3-hydroxypropyl)-amino]-2-methyl-3(2H)-pyridazinone is dissolved in ml of dichloromethane, and 2.1 ml (28.8 mmoles) of thionyl chloride are dropped to the solution. Then it is boiled for 3 hours under stirring and reflux cooling. The solvent is evaporated and the crude product thus obtained is triturated with ether. Thus 0.38 g (73%) of the desired compound is obtained. M.p.: 91°-92° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of (5-bromo-3-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (600 mg, 2.06 mmol) in dry DMF (20 mL), NaH (130 mg, 3.08 mmol) was added at 0° C. The solution was stirred vigorously for 10 minutes at 0° C. and MeI (180 μL, 2.88 mmol) was added. After 30 minutes, the reaction mixture was quenched with NH4Cl (saturated aqueous solution) and the product was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by Biotage using 3-15% EtOAc in hexane to afford title compound (470 mg) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=1.95 Hz, 1 H) 7.52 (dd, J=8.59, 1.95 Hz, 1 H) 3.22 (s, 3 H) 1.37 (s, 9 H)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[N:10][CH:9]=[CH:8][CH:7]=2.[H][H].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1>CN(C)C=O.O>[CH3:3][C:4]1[CH:13]=[C:12]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: Cc1cc(=O)c2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(COc2cc(C)nc3cccnc23)cc1
Reaction time: 16 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 80 mg) was added to a stirred suspension of the 1,5-naphthyridinone (D1) (320 mg) in N,N-dimethylformamide (DMF) (10 ml). The mixture was stirred until evolution of hydrogen had ceased and then a solution of the bromomethyl compound (C1) in DMF (2 ml) was added. Stirring was continued for 16 hours and then water (100 ml) was added. The mixture was extracted with ethyl acetate (3×25 ml) and the extracts were washed with water (25 ml), followed by saturated sodium chloride solution (25 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v) to give methyl 4'-[(2-methyl-1,5-naphthyridin-4-yloxy)methyl]biphenyl-2-carboxylate (A1) (244 mg), as an off-white powder, m.p. 132°-134° C. (from ethyl acetate/hexane); NMR (CDCl3): 2.7(s,3H), 3.6(s,3H), 5.5(s, 2H), 6.9(s,1H), 7.3-7.7 (complex m,3H), 7.85(d,1H), 8.3(dd,1H), 8.9(dd,1H); 13C NMR: (benzylic CH2) 70.6 ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[N:12]1([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=3)=[O:23])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.C1COCC1>[N:1]1([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:22]([N:19]3[CH2:20][CH2:21][C@H:17]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:18]3)=[O:23])=[CH:29][CH:28]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccc(CCl)cc1)N1CCC(N2CCCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cn2ccc3ccccc32)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A solution of indole (0.15 mmol, 19 mg) in a mixture of DMF/THF (1:4, 2 mL) is treated with sodium hydride (50 mg) followed by [1,3′]bipyrrolidinyl-1′-yl-(4-chloromethyl-phenyl)-methanone (0.15 mmol, 43 mg), stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (8 mg), identified by HPLC and mass spectral analyses. Retention time 1.86 min., MS [374.2 m/e (M+H)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(O)(=O)C.C(O[BH-](O[C:39](=[O:41])[CH3:40])OC(=O)C)(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:18][CH:19]=2)[C:39](=[O:41])[CH2:40]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 991.1 %

Procedure:
To a solution of N— (tert-butoxycarbonyl)ethylenediamine (5.0 g) and 4-(1H-imidazol-1-yl)benzaldehyde (5.35 g) in methanol (10 ml) was added acetic acid (300 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (318 mg), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The solution was extracted with water, and the aqueous layer was made alkaline with sodium hydroxide solution. The mixture was extracted with dichloromethane and dried with sodium sulfate, and sodium sulfate was filtered off. To the filtrate was added triethylamine (6.3 g) and then was added at 0° C. chloroacetyl chloride (3.53 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution washed with sodium bicarbonate solution and brine, dried and concentrated, and the residue was dissolved in DMF (100 ml). To the solution was added sodium hydride in oil (1.50 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried and concentrated, and the residue was purified with column chromatography (ethyl acetate) to give colorless amorphous of the title compound (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.75 g), 2-(2,4-dichlorobenzyl)-3-oxopentanoic acid methyl ester (1.3 g), polyphosphoric acid (5 mL) and dioxane (25 mL) was heated at 120° C. for 17 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and this mixture washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a brown oil, 1.7 μg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1ccccc1I
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-2-trifluoromethyl-benzene.
Reaction SMILES: [N:1]1([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(OC)C=CC=CC=1.N1(C2C=CC=CN=2)CCCC1.Cl[C:56]([O:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C(F)(F)F)=O>[CH2:59]([O:58][C:56]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:14]=1)(=[O:29])=[O:30])=[O:57])[CH2:60][CH2:61][CH3:62]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2cnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 36 %

Procedure:
To a solution of 3-[3-(2-benzoimidazol-1-ylacetyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (54.4 mg, 0.107 mmol; see step (b)) in TFA (3 mL) was added anisole (150 μL) and the reaction mixture was stirred for 28 h at ambient temperature. The reaction mixture was concentrated in vacuo and dried in vacuo overnight. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (31.6 mg, 0.214 mmol) and butyl chloroformate (135.7 μL, 1.07 mmol), and the reaction mixture was stirred overnight. Another portion of pyrrolidinopyridine (31.6 mg, 0.214 mmol) and butyl chloroformate (135.7 μL, 1.07 mmol) was added and the reaction mixture was stirred overnight. Citric acid (10 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound in 36% yield, over two steps, (21 mg, 0.038 mmol).