Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11](Br)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.[C:36]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:41]=[CH:40][C:39]([N:42]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:60][CH:59]=2)[C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([C:46]4[CH:45]=[CH:44][C:43]([N:42]([C:58]5[CH:59]=[CH:60][C:61]([C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)=[CH:62][CH:63]=5)[C:39]5[CH:40]=[CH:41][C:36]([C:70]6[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=6)=[CH:37][CH:38]=5)=[CH:48][CH:47]=4)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 73 °C
Reaction time: 10 h
Yield: 63.8 %

Procedure:
10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 6 (13.0 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amine (15.9 g) a toluene/ethanol (4/1, v/v) mixed solvent (250 ml), and a 2M potassium carbonate aqueous solution (51 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (2.1 g), and stirred at 73° C. for 10 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (1.7 L) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was cooled to a room temperature. A precipitated solid was collected by filtration and purified by recrystallization using 1,2-dichlorobenzene (1.7 L) to obtain a white powder of 10-(biphenyl-4-yl)-7-[4-bis(biphenyl-4-yl)amino-phenyl]-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (13.4 g; yield 63.8%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:34]1[N:39]([CH2:40][CH2:41][NH2:42])[CH2:38][CH2:37][O:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:42][CH2:41][CH2:40][N:39]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(4-morpholino)ethylamine employing methods similar to those described in Example 5. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). This procedure gave the product as an off-white rigid foam: 1H NMR (CDCl3) δ 10.46 (1H, br t, J˜6 Hz), 8.59 (1H, d, J=1.3 Hz), 8.12 (1H, s), 7.24 (2H, dd, J=8.6, 5.4 Hz), 7.00 (2H, t, J=8.6 Hz), 4.32 (2H, br t, J=7 Hz), 4.16 (2H, s), 3.98 (4H, br), 3.91 (2H, q, J=6 Hz), 3.77 (2H, br), 3.50 (4H, m), 3.39 (2H, t, J=6 Hz), 2.92 (2H, br), 2.41 (2H, t, J=8 Hz), 2.05 (2H, m); ES+ MS: 538 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH3:39][O:40][CH2:41][CH2:42]NC>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH2:42][CH2:41][O:40][CH3:39])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: CNCCOC
Product: COCCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using N-(2-methoxyethyl)methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=547, obsd.=547).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:18])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:18][CH3:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.38 g. of 1-[2-(2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. of hexamethylphosphoramide under nitrogen is added 480 mg. of a 56% dispersion of sodium hydride in mineral oil. After stirring for 1 hour at room temperature, the temperature is adjusted to 50° C. and stirring is continued for 1 to 2 hours. The reaction mixture is then cooled to about 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter, the solution is stirred at 5° to 10° C. for 1 hour, then at room temperature for 4 hours and then heated at 50° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue may be chromatographed on silica gel to effect purification of the free base. Elution of the gel with 5 to 10% methanol in dichloromethane yields 1-[2-(2-naphthyl)-2-(methoxy)ethyl]imidazole.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N>N1C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[O:6][CH2:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[CH2:9][NH:10][C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH3:2]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NCC(CO)c1cccc(C(F)(F)F)c1
Agent: N
Solvent: c1ccncc1
Product: CCNC(=O)OCC(CNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg (42 μmol) of 4-N,N-dimethylaminopyridine and 66 μl (0.84 mmol) of ethyl isocyanate were added to a solution of 134 mg (0.42 mmol) of the compound of Example 17A in 2.5 ml of pyridine. The mixture was stirred at RT overnight. A further 66 μl of ethyl isocyanate were then added, and the mixture was heated at 50° C. for 24 h. After cooling to RT, 0.5 ml of ammonia solution (35% in water) was added. The volatile components were removed on a rotary evaporator. A little acetonitrile and 1 N hydrochloric acid were added to the residue, and the solution was separated by preparative HPLC [Method 9]. This gave 110 mg (67% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][C@@H:9]1C[CH2:12][N:11]([CH3:14])[CH2:10]1)=[O:7].CN(C)CCN>>[CH3:14][N:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Agent: CN(C)CCN
Product: COc1cc(C(=O)NCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising N,N-dimethylethane-1,2-diamine (Aldrich; 818 mg, 9.28 mmol), as a brown solid (2.5 g, 100%)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](O)=[O:13].Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:25][O:24][N:23]([CH3:22])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:8])[CH:10]=1
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (7.6 mL, 54.65 mmol) was added slowly to a mixture of 3-methyl-4-nitrobenzoic acid (5 g, 27.33 mmol), N,O-dimethylhydroxylamine hydrochloride (2.99 g, 30.06 mmol), and EDCI (6.28 g, 32.79 mmol) in DCM (30 mL). The mixture was stirred at room temperature overnight, quenched with saturated aqueous NaHCO3 and stirred at room temperature for 30 minutes. Water (50 mL) was added followed by additional DCM. The mixture was stirred for 10 minutes and layers were separated. The aqueous layer was again extracted with DCM. The combined organic layer was dried over Na2SO4, then filtered. The solvent was removed and the residual oil chromatographed (DCM/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]2=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:50][C:51]1[CH:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[O:53][N:52]=1.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C(Cl)Cl>[CH3:50][C:51]1[CH:55]=[C:54]([C:2]2[N:7]=[C:6]3[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:9][O:10][C:5]3=[CH:4][CH:3]=2)[O:53][N:52]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: COC(=O)Cc1coc2ccc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1coc2ccc(-c3cc(C)no3)nc12
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A sealable flask was charged with methyl 2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate, palladium (II) acetate (49.8 mg, 222 μmol), X-Phos (211 mg, 443 μmol), and 3-methyl-5-(tributylstannyl)isoxazole (1319 mg, 3546 μmol). The flask was sealed and dioxane (20 mL) was added. The mixture was sparged with N2 for 10 min, then heated at 100° C. for 48 h. The mixture was cooled to rt and concentrated for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep®, pre-packed silica gel column (40 g) using 98:2 CH2Cl2:MeOH to 90:10 CH2Cl2: MeOH to afford methyl 2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate (581 mg, 96.3% yield). LRMS (ESI) m/z calcd for C4H113N2O4 (M+H) 273.1. found 273.3.
Reaction SMILES: [C:1]1(=O)[CH:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:4]2[CH2:3][NH:2]1.S(Cl)(Cl)=O.C1(=NO)C2CC3C=CC=CC=3C2C1>O1CCOCC1>[CH2:1]1[NH:2][CH2:3][CH:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH:5]12
Reactant: O=C1NCC2c3ccccc3CC12
Agent: ON=C1CC2c3ccccc3CC12
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: c1ccc2c(c1)CC1CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3a,8,8a-Tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one. Thionyl chloride (1.9 mL, 26.4 mmol) was added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime (1.5 g, 8.8 mmol) in 1,4-dioxane (44 mL), and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×50 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:25][NH:26][C:27]([NH2:29])=[S:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[N:25][NH:26][C:27]([NH2:29])=[S:28])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Yield: 51.5 %

Procedure:
1,3-bis-(4-fluorobenzoyl)benzene 12 (0.347 g, 1.08 mmol) was dissolved in anhydrous methanol (50 mL). The solution was heated at reflux for 15 min, and thiosemicarbazide (0.049 g, 0.54 mmol) and a catalytic amount of p-toluenesulfonic acid were added. After 10 h at reflux, the resulting solution was concentrated under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, 70:30) afforded the desired 1,3-bis-(4-fluorobenzoyl)benzene thiosemicarbazone (0.11 g, 0.278 mmol, 52% yield) as a white solid; 1H NMR (500 MHz, CDCl3): δ 8.67 (s, 1H, NH), 7.97 (m, 1H, ArH), 7.90 (m, 1H, ArH), 7.83 (m, 1H, ArH), 7.75 (m, 1H, ArH), 7.68 (m, 1H, ArH), 7.500 (m, 2H, ArH), 7.39 (s, 1H, NH2), 7.31 (m, 2H, ArH), 7.22 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 7.16 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 7.06 (ddd, J=8.5 Hz, 5.0 Hz, 3.0 Hz, 1H, ArH), 6.36 (s, 1H, NH2); HRMS (ESI) calculated for C21H15F2N3OSH (M+H)+ 396.0970, found 394.0834; HPLC retention time 13.740, 13.966 min.
Reaction SMILES: ClC1C=CC(S(N[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1C=CC(C2OC=CN=2)=CC=1F.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]3[O:67][CH:68]=[CH:69][N:70]=3)=[C:62](F)[C:61]=2[F:72])[C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[CH2:57][OH:58])(=[O:49])=[O:48])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]3[O:67][CH:68]=[CH:69][N:70]=3)=[CH:62][C:61]=2[F:72])[C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[CH2:57][OH:58])(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: Fc1cc(-c2ncco2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CO
Yield: 14 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (100 mg, 0.33 mmol), cesium carbonate (129 mg, 0.40 mmol), and 2-(4-(bromomethyl)-3-fluorophenyl)oxazole (101 mg, 0.40 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (22 mg, 14%). 1H NMR (400 MHz, CDCl3) δ ppm 7.63-7.86 (m, 6H), 7.44-7.51 (m, 2H), 7.24 (s, 1H), 4.60 (d, J=15.61 Hz, 1H), 4.38 (d, J=15.00 Hz, 1H), 3.63 (ddd, J=11.83, 4.78, 3.02 Hz, 2H), 3.00-3.11 (m, 1H), 2.57 (br. s., 1H), 1.55-1.70 (m, 3H), 1.43-1.54 (m, 2H), 0.95-1.19 (m, 4H). Analytical HPLC R.T.=23.89 min. MS [M+H]+=479. HRMS [M+H]+ calc'd 479.1208, found 479.1219. Chiral LC: R.T.=9.98 min., >98% ee.
Reaction SMILES: CC([CH:5]1[CH2:11][N:10](C([O-])=O)[CH2:9][C:8]2[CH:15]=[C:16]([C:19]3[CH:20]=[N:21][C:22]([NH2:28])=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=3)[CH:17]=[CH:18][C:7]=2[O:6]1)(C)C.[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[N+:25]([C:23]1[C:22]([NH2:28])=[N:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:7]3[O:6][CH2:5][CH2:11][NH:10][CH2:9][C:8]=3[CH:15]=2)[CH:24]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)C1CN(C(=O)[O-])Cc2cc(-c3cnc(N)c([N+](=O)[O-])c3)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 1,1-dimethylethyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.5 g, 9.1 mmol, example 26, step 1) in methanol (75 mL) and 4N hydrogen chloride in dioxane (11 mL) was stirred at 50° C. for 1.5 h and then concentrated. The resulting residue was triturated with a 10% methanol in diethyl ether solution (50 mL) to provide 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (3.1 g, 95%) as a red solid. 1H NMR (400 MHz, d6-DMSO) δ 9.76 (bs, 2H), 8.80 (d, 1H), 8.60 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H), 7.16 (d, 1H), 4.39 (bs, 2H), 4.25 (bs, 2H), 3.48 (bs, 2H); MS (EI) for C14H14N4O3: 287 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[Br:20]
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Cl)cc1

Procedure:
2-Bromo-(p-chlorophenyl)-acetic acid methyl ester was prepared from (4-chlorophenyl)-acetic acid methyl ester (2.5 g, 13.5 mmol) and NBS (2.52 g, 14.1 mmol) in CCl4.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>[Pd].C(O)C>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCC#CCCC(=O)O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCCCCC(=O)O
Reaction time: 14 h
Yield: 68 %

Procedure:
10% Palladium on carbon (10% wt) was added to a solution of oct-4-ynedioic acid I-56 in ethanol. The mixture was degassed with argon and then stirred under an atmosphere of H2 for 14 h. The mixture was filtered through celite and concentrated to afford octanedioic acid in 68% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[NH2:14][C@@H:15]1[C:20]2[CH:21]=[C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:23]=[CH:24][C:19]=2[O:18][C:17]([CH3:33])([CH3:32])[C@H:16]1[OH:34]>C(N(CC)CC)C>[F:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:14]([C@@H:15]1[C:20]3[CH:21]=[C:22]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH:23]=[CH:24][C:19]=3[O:18][C:17]([CH3:32])([CH3:33])[C@H:16]1[OH:34])[C:5]2=[O:7]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: COC(=O)c1cccc(F)c1CBr
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3c(F)cccc3C2=O)[C@@H]1O
Yield: 63.9 %

Procedure:
Following the procedure and working up described in Example 12, but using 0.272 g of methyl 2-bromomethyl-3-fluorobenzoate, 0.326 g of trans-4-amino-3,4-dihydro-2,2-dimethyl 6-trifluoromethylsulfonyl-2H-1-benzopyran- 3-ol and 0.15 ml of triethylamine, 0.294 g of the title compound, melting at 259°-261° C., was obtained after purification by column chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, followed by recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20]C[CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].CNCC[OH:29].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]([CH2:17][CH2:18][OH:29])[CH3:20])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CNCCO
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N(C)CCO)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30), 0.38 g. (0.005 mole) of 2-methylaminoethanol and 0.53 g. (0.005 mole) of sodium carbonate in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from ethyl acetate to afford 0.5 g. of product, m.p. 111°-113° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:38])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C)=[C:26]([F:37])[CH:25]=3)=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([C@H]1CC[C@H](CCCOC2C=CC(OC(=O)C3C=CC(OCCCCCCCC)=C(F)C=3)=CC=2)CC1)CCCC>>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:38])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:26]([F:37])[CH:25]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCOc1ccc(C(=O)Oc2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)cc1F
Agent: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)cc1F
Product: CCCCCOc1ccc(C(=O)Oc2ccc(OCCC[C@H]3CC[C@H](CCCCC)CC3)cc2)cc1F

Procedure:
4-hexyloxy-3-fluorobenzoic acid 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenyl ester; 4-octyloxy-3-fluorobenzoic acid 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenyl ester;