Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:30][CH2:29][C:14]3([C:19]4=[CH:20][CH:21]=[CH:22][N:18]4[C:17]4[CH:23]=[CH:24][C:25]([CH2:27][OH:28])=[CH:26][C:16]=4[O:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:12][CH2:13][C:14]3([O:15][C:16]4[CH:26]=[C:25]([CH:27]=[O:28])[CH:24]=[CH:23][C:17]=4[N:18]4[CH:22]=[CH:21][CH:20]=[C:19]34)[CH2:29][CH2:30]2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C=O)ccc2-n2cccc23)cc1OC

Procedure:
A solution of (4-ethyl-3-methoxy-phenyl)-[7′-(hydroxymethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (270 mg, 0.62 mmol) and manganese dioxide (270 mg, 3.1 mmol) in dichloromethane (5 mL) was stirred at 60° C. overnight. The reaction was filtered, evaporated and submitted to the next step without further purification. ESI-MS m/z calc. 430.5. found 431.7 (M+1)+; Retention time: 2.01 minutes (3 min run).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:32])[CH3:33])=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(OC(C)C)nc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(OC(C)C)nc2)cc1)C(=O)O
Yield: 85.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2-isopropoxypyridine-5-carbonylamino)ethoxy]phenyl]propionate (170 mg), which is the product of Example 53, was reacted with aqueous sodium hydroxide solution (1N, 0.75 ml) and the reaction mixture was treated to give the title compound (137 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=5)=[CH:3][C:4]=4[F:31])[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5)cc4F)CC3)n2CCS1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A solution of the compound (421 mg, 0.8 mmol) obtained in Example 14-5), 3-pyridylboronic acid (197 mg, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (185 mg, 0.16 mmol), and potassium carbonate (221 mg, 1.6 mmol) in dimethoxyethane (3.2 mL) and water (0.8 mL) was stirred at 100° C. for 6 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (344 mg, 82%) as a colorless solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]([F:31])([CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>COCCOC>[C:13]([C:12]([C:11]([C:10]([C:9]([C:8]([CH2:25][CH2:26][S:27]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])(=[O:29])=[O:28])([F:7])[F:31])([F:24])[F:23])([F:22])[F:21])([F:20])[F:19])([F:18])[F:17])([F:16])([F:15])[F:14]
Reactant: NCCCCl
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: COCCOC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl

Procedure:
3-chloropropylamine hydrochloride (6.0 g), diaza(1,3)bicyclo[5.4.0]-undecane (DBU, 4.1 g) and 1,2-dimethoxyethane (21.5 g) solvent were placed in the round bottom flask equipped with mechanical stirring under nitrogen. Solution of 2-(perfluorohexyl)ethanesulfonyl chloride CF3(CF2)5(CH2)2SO2Cl (10.1 g), in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 minutes at 20-25° C. while stirring at 250 rpm. Then additional DBU (2.6 g) was added. Reaction mixture was stirred for 2 h after the DBU addition was completed. The reaction was monitored by GC to ensure the complete conversion of 2-(perfluorohexyl)ethanesulfonyl chloride. The final reaction mixture was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane and combined filtrate was evaporated in vacuum to obtain 11.3 g of crude CF3(CF2)5(CH2)2SO2NH(CH2)3Cl as yellow solid. 9.5 g of the crude product was additionally dissolved in hot toluene (7 g) and washed with 14 mL of 2.5 wt % HCl aqueous solution, followed with 12 mL water wash. Toluene solution was evaporated in vacuum to obtain 8.35 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl (GC purity 93%, yield 88%).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2>N1C=CC=CC=1>[Br:1][C:13]1[CH:14]=[N:15][C:16]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:18][CH:17]=2
Reactant: Clc1ccc2ncccc2c1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2ncc(Br)cc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The synthesis was done by the same procedure as that of J. J. Eisch (J. Org. Chem. Vol. 27, p. 1318, 1962). Bromine (79 μl) and carbon tetrachloride (2 ml) were added to 6-chloroquinoline (250 mg) and stirred at 90° C. for two hours. Pyridine (123 μl) was added to the reaction solution and stirred at the same temperature for 16 hours. The reaction solution was concentrated and purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (250 mg).
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][CH:2]([C:3]1[O:4][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 2-hydroxy-3-methylbutanoic acid (70 mg, 0.6 mmol) in DMF (6 mL) were added DIPEA (0.125 mL, 0.7 mmol) and HATU (0.23 g, 0.6 mmol). After stirring at rt for 15 min 17 (0.2 g, 0.6 mmol) was added as a solution in DMF (2 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. The reaction was cooled to rt, purified by preparative LCMS to afford crude material, which was further purified by flash column chromatography on silica with DCM/2% MeOH as eluant to give 3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A64) as an off white solid. 1H NMR (400 MHz, CD4OD) δ 8.76 (s, 1H), 7.93 (s, 1H), 7.47 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.36 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 4.51 (d, J=6 Hz, 1H), 3.76 (s, 3H), 2.69 (s, 3H), 2.16 (m, 1H), 2.14 (s, 3H), 1.02 (d, J=6 Hz, 3H), 0.94 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18])=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
Magnesium chloride (221 mmol) and triethylamine (752 mmol) were added to a solution of diethyl malonate (375 mmol) in toluene (250 ml) and the reaction mixture was maintained for 1 h at 25° C. A solution of 2-chloronicotinoyl chloride (313 mmol) in toluene (80 mL) was added dropwise over the course of 2 h. The reaction mixture was maintained at rt for 3.5 h and was quenched with cold (0° C.) water (500 mL). The resulting solution was extracted with ethyl acetate (500 mL) and the organic layers combined. The organic layer was washed with brine (3×300 mL), dried (sodium sulfate), and was concentrated to provide diethyl 2-(2-chloronicotinoyl)malonate in 85% yield as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (60 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (79 mg, 0.23 mmol) in an analogous manner to Example 946 to afford an off-white solid (15 mg, 10%). LCMS (m/e) 575 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.65 (m, 1H), 7.51 (s, 1H), 7.30 (m, 1H), 6.88 (d, J=8 Hz, 1H), 3.71 (s, 3H), 3.62 (m, 2H), 3.35 (s, 3H), 3.20-3.05 (m, 4H), 2.76 (s, 6H), 2.62 (m, 1H), 2.27 (m, 1H), 2.00 (m, 2H), 1.51 (m, 1H) 1.28 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][S:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCSCCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCSCCc1ccccn1
Reaction time: 6 h
Yield: 63.5 %

Procedure:
A mixture of 2-[[2-(2-pyridinyl)ethyl]thio]ethanol (0.50 g), 1,6-dibromohexane (2.13 g), TAB (0.4 g) and 50% aqueous sodium hydroxide (6 ml) was stirred under nitrogen for 6 h, then diluted with water (75 ml) and extracted with diethyl ether (2×150 ml). The organic extracts were evaporated in vacuo to give an oil, which was partitioned between 2N hydrochloric acid (100 ml) and hexane (2×100 ml). The aqueous phase was basified to pH 12 with 50% aqueous sodium hydroxide and extracted with diethyl ether (2×150 ml), the dried organic extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with System F (1:1) gave the title compound (0.60 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.64
Reaction SMILES: [CH2:1]([NH:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([S:14]CC2C=CC(OC)=CC=2)[CH2:11][N:10]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])=[O:8])[CH:2]([CH3:4])[CH3:3].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([NH:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([SH:14])[CH2:11][N:10]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NNCC(C)C)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNNC(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 86.5 %

Procedure:
(step 2) 222 mg (0.42 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl-hydrazide in 10 ml TFA were treated with 0.68 ml (4.2 mmol, 10 eq) triethylsilane at 80° C. for 90 min. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography yielding 148 mg (86%) (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl hydrazide as light yellow crystalline, MS: 408 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3](=[CH2:18])[CH2:4][NH:5][C:6]1[CH:15]=[C:14]([O:16]C)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[ClH:19]>>[ClH:19].[ClH:19].[NH2:1][CH2:2][C:3](=[CH2:18])[CH2:4][NH:5][C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: C=C(CN)CNc1cc(OC)c2ccccc2n1
Agent: Cl
Product: C=C(CN)CNc1cc(=O)c2ccccc2[nH]1

Procedure:
The title compound was prepared according to the method described in Example 1(b) from 2-(2-aminomethylallylamino)-4-methoxyquinoline (70 mg, 0.29 mmol) and concentrated hydrochloric acid (2 mL) and was used without further purification. δH (CD3OD) 3.92 (2H, s), 4.53 (2H, s), 5.59 (2H, d, J=12.8), 6.61 (1H, d, J=0.9 Hz.), 7.65 (1H, dd, J=7.18 & 7.12 Hz), 7.93 (1H, dd, J=7.21 & 7.23 Hz), 8.02-8.16 (1H, m), 8.25 (1H, d, J=8.08 Hz); MS (ES+) 230 (31%) MH+ 213 (100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[N:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nn2)c1=O
Yield: 60.2 %

Procedure:
Following Example 188c, 3,5-dibromo-1-methylpyridin-2(1H)-one (536 mg, 2.0 mmol) and 330a (558 mg, 2.0 mmol) were reacted to give 330b as a yellow solid (560 mg, 60%). MS: [M+H]+ 467
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[F:20][C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[C:30](O)=[O:31]>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:22]3[N:23]=[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]4[C:21]=3[F:20])=[O:31])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1nc2ccccn2c1F
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccn2c1F
Yield: 37.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (0.084 g, 0.466 mmol). The product was purified by recrystallization from acetonitrile. Yield 37.9%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.30 (dd, 1H), 4.46 (dd, 1H), 4.59-3.69 (m, 1H), 6.62 (d, 1H), 6.91-6.96 (m, 1H), 7.24-7.29 (m, 1H), 7.52-7.56 (m, 2H), 7.76-7.80 (m, 2H), 7.94-7.97 (m, 1H), 8.08 (d, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:8]3[CH:17]4[NH:18][CH:14]([CH2:15][CH2:16]4)[CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.[CH3:26]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:8]3[CH:17]4[NH:18][CH:14]([CH2:15][CH2:16]4)[CH2:13][C:9]=3[N:10]([CH3:26])[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc2[nH]c3c(c12)C1CCC(C3)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(Br)cc31)C1CCC(C2)N1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Sodium hydride (38 mg, 0.950 mmol) was added to a solution of the product of step A (240 mg, 0.636 mol) in DMF (4 mL) at room temperature under N2. After 1 h, methyl iodide (134 mg, 0.058 mL, 0.943 mol) was added, and the reaction allowed to proceed for an additional 1 h. The mixture was quenched with H2O, upon which a solid precipitated out of solution. The solids were filtered off to provide tert-butyl 3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (248 mg, 100%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 5.30-5.10 (br m, 1H), 4.76-4.56 (br m, 1H), 3.54 (s, 3H), 3.49-3.19 (br m, 1H), 2.46 (d, J=16.0 Hz, 1H), 2.37-2.08 (m, 2H), 1.97-1.86 (m, 1H), 1.69-1.57 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:16][CH2:15][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To 4-[1-(2,4-Difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (420) (0.225 g, 0.564 mmol) in MeCl2 (2.0 mL) was added TFA (2.0 mL). The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness. The resulting residue was taken up in 1N HCl (30 mL) and washed with EtOAc (30 mL). The aqueous layer was made alkaline with 5N NaOH (10 mL) and the desired product was extracted into EtOAc. The organic phase was concentrated to dryness yielding 0.14 g (83%) pure product.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:21]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32]I)[CH2:28][CH2:27]1)[CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:32][C@H:29]3[CH2:30][CH2:31][C@H:26]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]3)=[C:14]([F:19])[C:13]=2[F:20])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(O)c(F)c2F)cc1
Reactant: CCCCC[C@H]1CC[C@H](CI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2ccc(OC[C@H]3CC[C@H](CCCCC)CC3)c(F)c2F)cc1

Procedure:
0.1 mol of 4'-n-pentyl-2,3-difluorobiphenyl-4-ol and 0.1 mol of trans-4-n-pentylcyclohexylmethyl iodide and heated in the presence of 0.12 mol of anhydrous K2CO3 in dimethylformamide (DMF) until the mixture boils gently. When the reaction has ended, the mixture is worked up in the customary manner and the product is purified by chromatography and crystallization. Trans-4-n-pentylcyclohexylmethyl 4'-pentyl-2,3-difluorobiphenyl-4-yl ether is obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([OH:13])=O)[O:4][CH2:3][CH2:2]1.C[O-].[Na+].S(Cl)([Cl:19])=O>CO.C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([Cl:19])=[O:13])[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC12OCCO2
Reactant: O=S(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCCCC12OCCO2
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decane-6-carboxylic acid (2.42 g, 13 mmol) in methanol (6 mL) was added a 5.4 N solution of sodium methoxide in methanol (2.41 mL). The mixture was stirred at 20° C. for 20 min and the solvent was then evaporated under reduced pressure. Toluene (20 mL) was added to the residue and the solvent was evaporated under reduced pressure. The white solid obtained (2.5 g) was suspended in toluene (13 mL) and thionyl chloride (1 mL, 13.8 mmol) was added to the stirred solution at 20° C. over 10 min. Stirring was continued at 40° C. for 1 h when gas evolution stopped to give a ca 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]([N:12]1[CH2:16][C@@H:15]2[CH2:17][CH2:18][CH2:19][C@@H:14]2[C@H:13]1[C:20](O)=[O:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:55][C@@H:56]([CH2:65][CH2:66][CH3:67])[CH:57]([OH:64])[C:58]([NH:60][CH:61]1[CH2:63][CH2:62]1)=[O:59].Cl.N[C@@H](CCC)C(O)C(NC1CC1)=O>ClCCl.CN(C)C=O.O>[CH:61]1([NH:60][C:58](=[O:59])[CH:57]([OH:64])[C@@H:56]([NH:55][C:20]([C@@H:13]2[C@H:14]3[CH2:19][CH2:18][CH2:17][C@H:15]3[CH2:16][N:12]2[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:65][CH2:66][CH3:67])[CH2:63][CH2:62]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)O)C(C)(C)C
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(O)C(=O)NC1CC1

Procedure:
The crude (1S,3aR,6aS)-2-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid from Example 10 was dissolved in dichloromethane (4 mL) and treated with 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (71 mg, 2 eq), 1-hydroxybenzotriazole (HOBT) (57 mg, 2 eq) and N-methyl morpholine (0.2 mL, 5 eq) at room temperature. To this mixture was added after 30 minutes (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide, the compound of formula (12) (1 eq) in dichloromethane (3 mL) and N,N-dimethylformamide (3 mL) and the reaction mixture was stirred at room temperature. After 18 hours the reaction mixture was diluted with water, and the product extracted into ethyl acetate. The organic extract was washed with brine, dried and evaporated to dryness under reduced pressure, to give crude tert-butyl (2S)-1-((1S,3aR,6aS)-1-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)hexahydrocyclopenta-[c]pyrrol-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate, the compound of formula (17).