Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9](=[O:35])[CH2:10][C@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].Cl>O1CCOCC1>[CH3:34][S:31]([N:28]1[CH2:27][CH2:26][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:8]3[C:3](=[O:2])[NH:4][N:5]=[CH:6][CH:7]=3)=[O:35])=[CH:20][CH:21]=2)[CH2:30][CH2:29]1)(=[O:33])=[O:32]
Reactant: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1[C@H](CC(=O)c1ccn[nH]c1=O)c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 80 °C
Yield: 112.6 %

Procedure:
To a solution of (R)-1-(3-methoxypyridazin-4-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-3-o-tolylpropan-1-one (example 12, step 4; 50 mg, 0.10 mmol) in 1,4-dioxane (1.5 mL) was added 37% aq. hydrochloric acid solution (0.17 mL, 2.0 mmol) and the resulting solution was heated at 80° C. for 2½ h, then after cooling partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (54 mg), which was directly used in the next step. Colorless gum, MS: 480.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.O[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[C:16]1([CH:12]2[C:4]3[C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=3[O:15][C:13]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C(O)C(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccccc1
Yield: 37 %

Procedure:
Using 2,3,5-trimethylphenol and hydroxy(phenyl)acetic acid, the title compound was synthesized in the same manner as in Reference Example 2. Yield 37%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[NH2:10][C@H:11]([C:13]([N:15]1[C:21](=[O:22])[CH:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[C:28]([NH2:32])=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:14])[CH3:12]>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([NH:10][C@H:11]([C:13]([N:15]1[C:21](=[O:22])[CH:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[C:28]([NH2:32])=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:14])[CH3:12])=[O:4]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CCCCC(C)C(=O)O
Product: CCCCC(C)C(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21

Procedure:
Following General Procedure C-P above using 2-methylhexanoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 422 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 79%).
Reaction SMILES: [N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[OH-:21].[Li+]>CO>[C:2]([CH2:3][O:4][CH2:5][CH2:6][NH:1][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])([OH:21])=[O:7]
Reactant: COC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: O=C(O)COCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate are dissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol) 1-molar lithium hydroxide solution. The mixture is stirred for 2 hours at ambient temperature. Then it is evaporated down i. vac., the residue is diluted with water, cooled in the ice bath and acidified with 2-molar hydrochloric acid. After 10 minutes cooling in the ice bath the precipitate formed is filtered off, washed with water until neutral and dried at 50° C. in the drying cupboard.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23]([OH:25])=O)[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[CH2:83][C@@H:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[O:81][C:80]1=[O:93]>CN(C=O)C.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C@H:82]1[O:81][C:80](=[O:93])[N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:25])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[CH2:83]1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@H]2NC(=O)[C@H]2N)C(=O)O1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H]1CN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)O1
Yield: 71.4 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (1.29 g, 2.28 mmol) and HATU (909 mg, 2.39 mmol) in DMF:DCM (3:1, 9.0 mL) at 0° C. was added DIPEA (1.0 mL, 5.72 mmol). After 15 min of stirring at 0° C. tert-butyl (((R)-3-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2-oxooxazolidin-5-yl)methyl)carbamate (715 mg, 2.28 mmol) was added as a solution in DMF:DCM (1:1, 9 mL) followed by a DMF (1.5 mL) wash. After 1.2 h at rt it was diluted with EtOAc and washed with LiCl (5% aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl (5% aq), NaHCO3 (aq satd), brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 5-90%) to afford the title compound (1.357 g, 72%) as a white solid. LCMS: Rt=1.04 min, m/z=834.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccnc(N2CCC(CO)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCC(COS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-(4-Methylpyridin-2-yl)piperidin-4-yl)methanol (0.970 mmol, 0.2 g) and triethylamine (2.91 mmol, 0.404 mL, 0.294 g) were stirred in DCM at 0° C. Methanesulfonyl chloride (1.454 mmol, 0.113 mL, 0.167 g) was added dropwise and the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated in vacuo to afford (1-(4-methylpyridin-2-yl)piperidin-4-yl)methyl methanesulfonate. (0.234 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(N(CC)CC)C.[CH:27](=O)[CH2:28][CH2:29][CH3:30].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH2:27]([NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC=O
Reactant: Cc1cc(CCN)ccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCNCCc1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
138 mg 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate, 210 μl triethylamine and 50 μl Butyraldehyde were dissolved in 5 ml methanol. 150 mg molecular sieves 4 Angström were added and the mixture was stirred at room temperature overnight. Then 21 mg sodium borohydride were added and the mixture was stirred for an additional hour at room temperature. 50 ml ethyl acetate were added, and the reaction was quenched by addition of 0.5 ml water. The reaction mixture was filtered through a pad of celite and MgSO4. The filtrate was evaporated in vacuo to provide 230 mg crude 4-(2-Butylamino-ethyl)-2-methyl-benzonitrile, impurified with salts. This material was used without further purification.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:27]1[CH2:31][CH2:30][CH:29]([C:32]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:33])[CH2:28]1)[CH3:26]
Reactant: CCC1CCC(C(=O)O)C1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CCC(CC)C3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.5 g of 3-ethyl-cyclopentanecarboxylic acid and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OC(C)COc2ccccc2OC)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and N-ethylpiperazine (222 mg, 1.94 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (67%) of the title product. HRMS m/z calcd for C20H28N4O3(M)+372.2161, found 372.2174. Anal. (C20H28N4O3) C, H, N.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:13]([C:14]([C:16]3([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17]3)=[O:15])[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[CH3:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)[CH:33]=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].ClCCl>C1COCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:10][C@@H:11]([S:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:37][C:38]=3[C:43]([F:46])([F:44])[F:45])[CH2:12][N:13]2[C:14]([C:16]2([C:19]([F:21])([F:22])[F:20])[CH2:17][CH2:18]2)=[O:15])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)NC2(C#N)CC2)N(C(=O)C2(C(F)(F)F)CC2)C1
Reactant: Cc1cc(-c2ccc(S)c(C(F)(F)F)c2)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methanesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (20.5 g, 50 mmol) and 4-(2-methyl-pyridin-4-yl)-2-trifluoromethyl-benzenethiol hydrochloride (17.6 g, 57.5 mmol) in THF (75 mL) was added at 0° C. 25% sodium tert-butoxide in THF (43.2 g, 112.5 mmol) over 30 min and the reaction mixture was stirred at 50° C. for 4.5 h. After cooling to 10° C., the reaction mixture was added to dichloromethane (250 mL) and washed twice with deionized water (2×250 mL). The organic layer was dried (Na2SO4), filtered, and evaporated by rotary evaporation (45° C./≧10 mbar), affording the crude title product (30.9 g, 106%) as a beige, amorphous foam which was used without further purification in the next step. 1H NMR (CDCl3, 400 MHz) δ 1.10-1.35 (m, 6H), 1.47-1.58 (m, 2H), 2.00-2.11 (m, 1H), 2.65 (s, 3H), 2.92-3.01 (m, 1H), 3.92 & 4.02 (ABC, JAB=11.8 Hz, JAC=5.0 Hz, JBC=6.2 Hz, each 1H), 4.17 (quint, J=5.5 Hz, 1H), 4.72 (dd, J1=8.1 Hz, J2=4.8 Hz, 1H), 7.31 (dd, J1=5.1 Hz, J2=1.5 Hz, 1H), 7.37 (s, 1H), 7.62 (s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.80 (dd, J1=8.1 Hz, J2=1.9 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 8.60 (d, J=5.1 Hz, 1H). ESI-MS (m/z) [M+H]+ 583 (40).
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@@:34]3([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:38](=[CH2:40])[C@@H:37]4[C@H:35]3[C@H:36]4[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:25]1[C:26]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@@:34]3([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:38]4([CH2:2][CH2:40]4)[C@@H:37]4[C@H:35]3[C@H:36]4[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:32])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OCC1c3ccccc3-c3ccccc31)(C(=O)OCC)CC21CC1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
Add a solution of trifluoroacetic acid (2.66 g, 23.3 mmol) in dichloromethane (11.7 mL) dropwise over 5 minutes to a stirred solution of diethyl zinc 1M in heptanes (23.3 mL, 23.3 mmol) in dichloromethane (11.7 mL) cooled to 0-5° C. under nitrogen (exothermic reaction). After 10 minutes, add a solution of diiodomethane (6.25 g, 23.3 mmol) in dichloromethane (11.7 mL). After 10 minutes, add a solution of diethyl (1S,2S,5R,6S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (3.70 g, 7.8 mmol) in dichloromethane (11.7 mL). After 2 hours at 0° C., allow to warm to room temperature and stir for 16 hours. Quench the reaction mixture with cold 0.5M hydrochloric acid (50 mL) and dichloromethane (20 mL) and stir vigorously. Separate the dichloromethane layer via a hydrophobic frit and then evaporate to a pale yellow oil. Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a colorless oil (3.49 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) taking the centre cut fractions to give a colorless foam of title compound (2.12 g, 56%). MS (m/z): 490 (M+1). A second lot of product from the less pure fractions is obtained by repeated chromatography (363 mg, additional 9%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCN(C)CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
A flask containing 1-methyl-N-[4-(4morpholinylmethyl)phenyl]-4-piperidinamine (0.52 g) is treated with diethyl ethoxymethylenemalonate (0.55 mL). The flask is tightly capped and heated to 150° C. for 1 hour. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.55 mL) and heated to 180° C. for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 5% to 20% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.75 g of diethyl 2-{[(1-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)anilino]methylene}malonate as tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:40][CH2:39][C:34]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:33][CH:32]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5]([C:31]2[CH2:40][CH2:39][C:34]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:33][CH:32]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCC4(CC3)OCCO4)cnc2N)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (5.17 g, 46.2 mmol) in DME (115 mL) were added 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (15.36 g, 57.7 mmol), PdCl2(dppf).CH2Cl2 adduct (1.885 g, 2.309 mmol), and then 2 M aqueous solution sodium carbonate (19.57 g, 185 mmol). The reaction mixture was heated at 100° C. overnight. LCMS indicated the reaction was completed. The reaction was cooled down. To the mixture was added 1000 mL of EtOAc and 300 mL of water. The resulting mixture was stirred for 30 min, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×200 mL). The organic layers were combined, washed with water three times and brine, dried over sodium sulfate, filtered off, and concentrated in vacuo. The crude product was triturated by ether to provide tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (19.5 g, 45.6 mmol, 99%) as a light yellow solid. LCMS (m/z): 428.1 (MH+), 1.02 min.
Reaction SMILES: Cl.C([O:4][C:5](=[O:34])[CH:6]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[NH:7][C:8](=[O:27])[NH:9][NH:10][C:11](=[O:26])[C:12]1[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[C:14]([O:22]C(=O)C)[CH:13]=1)C.C(N)(=O)C.Cl>[OH-].[Na+]>[NH2:33][C:30]1[S:31][CH:32]=[C:28]([CH:6]([NH:7][C:8](=[O:27])[NH:9][NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:22])[CH:13]=2)[C:5]([OH:34])=[O:4])[N:29]=1
Reactant: CCOC(=O)C(NC(=O)NNC(=O)c1ccc(OC(C)=O)c(OC(C)=O)c1)c1csc(N)n1
Agent: CC(N)=O
Agent: Cl
Agent: [Na+]
Product: Nc1nc(C(NC(=O)NNC(=O)c2ccc(O)c(O)c2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 37 ml of 1N aqueous sodium hydroxide solution was dispersed 6.02 g of crystals of 2-(2-amino-1,3-thiazol-4-yl)-2-[3-(3,4-diacetoxybenzoyl)carbazoylamino]acetic acid ethyl ester.hydrochloride containing acetamide according to Reference example 61, and the mixture was stirred at room temperature for 1.5 hours. During stirring, crystals were dissolved completely. To this mixture was added 2N hydrochloric acid while stirring, and pH of the mixture was adjusted to 3.5. After further stirring for 10 minutes, precipitated crystals were collected by filtration, and the residue was washed well with water and vacuum dried over phosphorus pentoxide to obtain 1.36 g (Yield: 50.2%) of pale yellow crystals of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:27][N:28]([CH3:44])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](C(O)=O)=[CH:35]2.CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:44])[CH3:27])=[CH:40][CH:39]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Yield: 66.8 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, the reaction of the product with the above 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (210 mg, 0.74 mmol), EDCI.HCl (345 mg, 1.80 mmol) and DMA (3 mL) gave crude material that was purified by precipitation from a CH2Cl2 solution at 20° C. with iPr2O (2×) to give 14e (237 mg, 67%), mp 224-227° C. 1H NMR [(CD3)2SO] δ 11.72 (d, J=1.5 Hz, 1 H, NH), 9.16 (s, 1 H, H-4), 8.35 (dd, J=7.2, 2.5 Hz, 1 H, H-6), 8.23 (dd, J=6.9, 2.5 Hz, 1 H, H-9), 7.79-7.71 (m, 1 H, H-7,8), 7.41 (d, J=8.9 Hz, 1 H, H-7'), 7.21-7.16 (m, 2 H, H-3',4', 6.94 (dd, J=9.0, 2.4 Hz, 1 H, H-6'), 4.93 (dd, J=10.6, 9.8 Hz, 1 H, H-2), 4.70 (dd, 10.9, 2.4 Hz, 1 H, H-2), 4.65-4.58 (m, 1 H, H-1), 4.18-4.09 (m, 2 H, CH2Cl), 4.07 (t, J=5.9 Hz, 2 H, OCH2), 2.66 (t, J=5.8 Hz, OCH2CH2), 2.24 (s, 6 H, N(CH3)2).