Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[CH:28]1[C:44]2[C:43]3[C:42]4[C:41]5[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=5[CH:39]=[CH:38][C:37]=4[NH:36][C:35]=3[CH:34]=[CH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[C:14]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:36]4[C:37]5[CH:38]=[CH:39][C:40]6[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=6[C:42]=5[C:43]5[C:44]6[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=6[CH:33]=[CH:34][C:35]4=5)=[CH:7][CH:6]=3)=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc2c(c1)ccc1[nH]c3ccc4ccccc4c3c12
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccc6ccccc6c5c5c6ccccc6ccc54)cc3)c3ccccc23)cc1
Yield: 68.9 %

Procedure:
In a 100 mL three-neck flask were placed 2.3 g (5.6 mmol) of 9-(4-bromophenyl)-10-phenylanthracene, 1.5 g (5.6 mol) of 7H-dibenzo[c,g]carbazole, and 1.2 g (12 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 30 mL of toluene and 2.8 mL of tri-(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 0.16 g (0.28 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 17 hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was removed by suction filtration. The collected solid was dissolved in about 30 mL of hot toluene, and this solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). A solid obtained by concentration of the filtrate was recrystallized from toluene/hexane to give 2.3 g of a pale yellow powder, which was the object of the synthesis, in a yield of 70%. A reaction scheme (c−1) of Step 3 is illustrated below.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:31][CH2:32][CH3:33])[C:29]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=O)C=C(OCC)C=1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:32]([O:31][C:28]1[CH:27]=[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH2:24][OH:25])[CH:17]=3)[CH2:12][CH2:13]2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:29]=1[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)[CH3:33]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxymethyl-5-methoxy-N-piperidin-4-yl-benzamide (example 217) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 537.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:8]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:11]=2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:23]1([C:8]2[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:30][CH:29]=3)=[CH:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:14][CH:13]=3)[N:9]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(-n2cc(Cc3ccc(Br)cc3)c(C3CCCCC3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cn(-c3ccc(OC(F)(F)F)cc3)nc2C2CCCCC2)cc1
Temperature: 75 °C

Procedure:
A mixture of 0.75 g 4-(4-bromobenzyl)-3-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step D Example 13, 110 mg zinc cyanide, and 90 mg tetrakis(triphenylphosphine)palladium(0) in 5 mL DMF was heated under nitrogen in a 75° C. oil bath over night. Evaporate most of DMF. The residue was purified on silica gel using 10˜40% EtOAc in hexanes to give the title compound as a colorless gel. 1H NMR (CDCl3, 500 MHz) δ 7.64˜7.65 (m, 2H), 7.62˜7.64 (m, 2H), 7.50 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.26˜7.29 (m, 2H), 3.94 (s, 2H), 2.58 (tt, J=3.1 & 11.9 Hz, 1H), 1.82˜1.87 (m, 4H), 1.72˜1.76 (m, 1H), 1.58˜1.67 (m, 2H), 1.28˜1.38 (m, 3H). LC-MS: 2.67 min. (M+H=426).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]2[CH:20]=[CH:21][S:22][C:10]=12.[OH-].[K+]>O>[CH3:5][N:12]1[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:8])[C:10]2[S:22][CH:21]=[CH:20][C:11]1=2
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethyl sulphate (3.9 ml) was added to a stirred solution of ethyl 7-hydroxythieno[3,2-b]-pyridine-6-carboxylate (4.63 g) and potassium hydroxide (3.5 g) in water (50 ml) at 0°-5°. More water (20 ml) was added and the mixture was stirred at ambient temperature for 24 hours. The solid product was collected by filtration, washed with water and dried to give the novel compound ethyl 4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 122°-128°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[Br:18])(=O)=O.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N#N>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].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>[Br:18][C:8]1[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:12]([C:13](=[O:15])[CH3:14])[CH:11]=[C:10]([Cl:16])[C:9]=1[CH3:17]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1ccccc1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
A biphasic solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyl trifluoromethanesulfonate (3.3 g, 8.3 mmol) and phenylboronic acid (1.2 g, 10 mmol) in toluene (30 mL) and saturated sodium bicarbonate in water (30 mL) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (0.385 g, 0.333 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 80° C. for 2 hours. After cooling to r.t., the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column, eluting with 0-20% of ethyl acetate in hexane, to give the desired product (2.5 g, 93%). LCMS calculated for C15H13BrClO (M+H)+: m/z=323.0. found: 323.0.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([Cl:18])[CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([Cl:18])[CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\O[C@H]1CC[C@H](Cl)CC1)C(=O)CBr
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](Cl)CC1)c1csc(N)n1

Procedure:
Ethyl 4-bromo- (Z)-2-(trans-4-chlorocyclohexyloxyimino)-3-oxobutyrate (730 mg) was treated with thiourea as described in Example 4d, to give the title compound (579 mg, 85%) m.p. 155° C. (ethyl acetate-hexane) (Found: C, 47.05; H, 5.02; N, 12.75; Cl, 10.8; S, 9.73. C13H18N3CLO3S requires C,47.1; H, 5.4; N, 12.7; Cl, 10.7; S, 9.7%). νmax (Nujol) 3450, 3430, 3250, 3125, 1720, 1615, 1610, and 1540 cm-1, νH (CDCl3), 1.36 (3H, t, J 7.1 Hz), 1.73 (4H, m), 2.13 (4H, m), 4.18 (1H, m), 4.39 (2H, q, J 7.1 Hz), latter signal obscures single hydrogen multiplet, 5.5 (2H, s, exch. D2O), and 6.71 (1H, s).
Reaction SMILES: N[C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.N([O-])=O.[Na+].[ClH:18]>[Cu]>[Cl:18][C:2]1[C:3]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cl
Reactant: Cc1cnc(CCCCN)c(N)c1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cnc(CCCCN)c(Cl)c1

Procedure:
Reaction of 3-amino-2-(4-aminobutyl)-5-methylpyridine from Example 1(d) (0.5 g) with sodium nitrite, cuprous chloride, copper bronze and hydrochloric acid under conditions analogous to those of Example 1(e) gave 3-chloro-2-(4-aminobutyl)-5-methylpyridine (0.43 g) as an oil. N.M.R. (CDCl3) assignment δ(p.p.m.), multiplicity; NH2, 1.56, s; CH2 (CH2)2CH2NH2, 1.4-1.9, m; 5--CH3, 2.29, s; --CH2NH2, 2.74; m; --CH2 (CH2)3NH2, 2.91, m; 4H+6H pyridyl protons, 7.45+8.24, m×2;
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([I:11])=[CH:6][C:5]=1[O:12][CH3:13].[OH-].[Na+]>CO>[Cl:10][C:8]1[C:7]([I:11])=[CH:6][C:5]([O:12][CH3:13])=[C:4]([CH:9]=1)[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(I)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(I)c(Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
5-Chloro-4-iodo-2-methoxy benzoic acid methyl ester of Step B (3.00 g, 9.19 mmol) and sodium hydroxide (1.10 g, 27.6 mmol) were combined in methanol (92 mL) and the mixture refluxed for 12 hours. The reaction was cooled to room temperature and solvent evaporated. The residue was dissolved in 1 N sodium hydroxide (75 mL), washed with diethyl ether and the organic washings discarded. The aqueous phase was acidified with 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title carboxylic acid (2.64 g) as orange crystals, m.p. 150–151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH:16]([N:19](C(C)C)CC)(C)C.Cl.CN>O1CCCC1>[CH3:16][NH:19][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxybenzoyl chloride) (2.9 g, 17.0 mmol) and tetrahydrofuran (170 mL) and cool to 0° C. Add diisopropylethylamine (5.92 mL, 34 mmol). Add methylamine hydrochloride (1.26 g, 18.7 mmol). Allow to stir for 1 hour and concentrate in vacuo. Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane to give N-methyl-3,4,5-trimethoxybenzamide: TLC Rf =0.45 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.CN(C)[CH2:19][CH2:20]CN=C=NCC.C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:19]([O:14][C:13](=[O:15])[CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Yield: 93.3 %

Procedure:
In an oven-dried 250 mL round bottom flask under nitrogen, a mixture of (1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-azetidinyl)acetic acid (10 g, 46.5 mmol) in diethyl ether (100 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.80 g, 51.1 mmol), 4-(dimethylamino)pyridine (0.568 g, 4.65 mmol), and ethanol (5.97 mL, 102 mmol) at room temperature and the white mixture was stirred over the weekend. The white reaction mixture became a colorless solution with gummy material at the bottom of the flask after 1 h. The reaction mixture was diluted with ether (300 mL) and washed with 1M aq NaHSO4 solution (150 mL) and saturated aq NaHCO3 solution (150 mL). The organic phase was isolated, dried over MgSO4, and concentrated in vacuo to give the title compound (10.55 g, 93%) as a clear colorless liquid. MS(ES)+ m/e 244.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:17]([OH:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1[C@@H](c2cccc(Cl)c2)Oc2ccccc2[C@@H]1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1c2ccccc2O[C@H](c2cccc(Cl)c2)[C@H]1O
Temperature: 23 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a solution of (2R,3S,4S)-2-(3-chlorophenyl)chromane-3,4-diol (9) (28 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added manganese dioxide (44 mg, 0.5 mmol). The mixture was stirred at 23° C. for 24 h, filtered through a plug of Celite®, and concentrated under reduced pressure. The crude was purified by flash chromatography using 7% EtOAc/hexanes to afford 10 as a solid (16 mg, 59%). Analytical data for 9: 1H NMR (500 MHz, CDCl3) δ 7.93 (dd, J=7.9, 1.7 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.58 (ddd, J=8.6, 7.2, 1.8 Hz, 1H), 7.48-7.45 (m, 1H), 7.42-7.38 (m, 2H), 7.14 (ddd, J=8.0, 7.2, 1.0 Hz, 1H), 7.07 (dd, J=8.4, 1.0 Hz, 1H), 5.12 (d, J=12.3 Hz, 1H), 4.57 (dd, J=12.3, 1.9 Hz, 1H), 3.70 (d, J=1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 193.8, 161.5, 138.3, 137.1, 134.6, 129.9, 129.4, 127.6, 127.4, 125.8, 122.4, 118.4, 118.1, 83.0, 73.6; IR (film): 3461, 2921, 2851, 2361, 2341, 1695, 1608, 1579, 1466, 1300, 1229, 1138, 1104, 1009, 861, 764, 693, 419, 405 cm−1; LRMS (ESI): Mass calculated for [M+H]+ C15H12ClO3: 275.0; found 275.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCc1ccc(N)cc1Cl
Product: CCN(CC)CCc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-(2-diethylamino-ethyl)-phenylamine (Z44d). The reaction mixture was poured onto ice water and the aqueous phase was extracted with EtOAc. The org. phase was dried over sodium sulphate and evaporated down i. vac. The residue was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 5:2→1:1).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid methyl ester (1.28 g, 3.52 mmol) in tetrahydrofuran (12 mL) was treated with a 0.8M aqueous lithium hydroxide solution (4.9 mL, 3.88 mmol). The reaction mixture was stirred at 25° C. for 24 h and then concentrated in vacuo to remove tetrahydrofuran. The resulting yellow oil was partitioned between water (50 mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous hydrochloric acid solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (1.09 g, 99%) as a viscous yellow oil that solidified upon sitting to a white solid: mp 86-88° C.; EI-HRMS m/e calcd for C15H17F3O4S (M+) 350.0800, found 350.0792.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10](Cl)[N:9]=[CH:8][N:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[N:7]1[C:6]2[O:5][CH2:4][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=[N:9][CH:8]=1
Reactant: COC(=O)COc1ncnc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: O=C1COc2ncncc2N1
Temperature: 25 °C

Procedure:
In a 25 ml flask, (6-chloro-5-nitro-pyrimidin-4-yloxy)-acetic acid methyl ester (280 mg, 1.1 mmol) and tin tetrachloride (849 mg, 4.5 mmol) were dissolved in hydrochloric acid (7 ml) and heated for 1 hour at 80□. The reaction mixture was cooled to room temperature and neutralized by adding 10% sodium hydroxide solution dropwise, and the formed solid was removed by filtration. The filtrate was extracted with ethyl acetate, and the combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The obtained yellow solid mixture (107 mg) was used in the next step without further purification.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.NC.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:15]=1[N:25]([CH3:45])[C:26]([C:28]1[S:44][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([C:41]([OH:43])=O)=[CH:37][C:33]=3[O:34][CH2:35][CH2:36][C:30]=2[CH:29]=1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:15]=1[N:25]([CH3:45])[C:26]([C:28]1[S:44][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([C:41]([NH:3][CH3:2])=[O:43])=[CH:37][C:33]=3[O:34][CH2:35][CH2:36][C:30]=2[CH:29]=1)=[O:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIPEA (16.83 g, 130.2 mmol) was added to a suspension of H2NMe.HCl (5.02 g, 74.4 mmol) in THF (180 mL) and stirred at room temperature for 0.5 h. 2-((2-Chloro-4-(dimethylcarbamoyl)phenyl)(methyl) carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (9.00 g, 18.6 mmol) and HATU (21.22 g, 55.8 mmol) were added into the suspension separately. The reaction mixture was stirred at room temperature for 2 h. Concentrated to remove solvent, the resulting mixture was dissolved in CH2Cl2 (200 mL), washed by 2N HCl (200 mL), water (100 mL), and dried over Na2SO4. The crude product was purified by silica gel chromatography eluted with CH2Cl2:MeOH=10:1 (3.70 g, 40%) to furnish 223. ESI-MS: 498. 1H NMR (CDCl3, 400 MHz): δ7.58 (s, 1H, ArH), 7.42-7.29 (m, 4H, ArH), 6.92 (s, 1H, ArH), 6.34 (d, J=4.0 Hz, 1H, NH), 4.20 (t, J=5.0 Hz, 2H, CH2), 3.37 (s, 3H, CH3), 3.12 (s, 3H, CH3), 3.04-2.98 (m, 8H, CH2, 2CH3).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH2:21]([S:23]([N:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1)(=[O:25])=[O:24])[CH3:22]
Reactant: O=C(Nc1nc2cccc(-c3cn[nH]c3)n2n1)C1CC1
Reactant: CCS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)n1cc(-c2cccc3nc(NC(=O)C4CC4)nn23)cn1
Reaction time: 8 h

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (WW-060) (0.05 g, 0.186 mmol) in acetonitrile (2 mL), ethanesulfonyl chloride (0.022 ml, 0.224 mmol) and triethylamine (0.052 mL, 0.373 mmol) were added successively and the mixture was stirred overnight. After concentration under reduced pressure water was added and extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparatory HPLC. LCMS method: 1, RT: 3.87 min; MI: 361 [M+1]; NMR 1H (DMSO): 0.81-0.95 (m, 4H), 1.15 (t, 3H), 1.94 (brs, 1H), 3.82 (q, 2H), 7.66 (d, 1H), 7.73 (t, 1H), 7.81 (dd, 1H), 8.99 (s, 1H), 9.46 (s, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:7](=[O:9])[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(=O)NC(CC(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(CC(=O)Nc1ccccc1Oc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31.3 %

Procedure:
To a pre-stirred solution of N-acetyl-3-phenyl-β-alanine (104 mg, 0.50 mmol), EDC (265 mg, 1.38 mmol), triethylamine (70 mg, 0.69 mmol) and DMAP (6 mg, 0.046 mmol) in anhydrous DCM (25 ml), was added 2-(4-chlorophenoxy)phenylamine (100 mg, 0.46 mmol). This mixture was then allowed to stir at room temperature for 14 h. The reaction mixture was washed with 2.5M NaOH (20 ml), 2M HCl (20 ml) and the organics were then dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (eluant; DCM to 9:1 DCM:MeOH) then proceeded to afford the desired product as an off-white solid (58.9 mg, 31%). 1H NMR (270 MHz, CDCl3): δ 2.03 (3H, s, CH3), 2.83-2.99 (2H, m, CH2), 5.30-5.40 (1H, m, CH), 6.73-6.77 (1H, dd, J=1.5, 8.2 Hz, Ar—H), 6.83-6.86 (2H, m, Ar—H), 6.95-7.03 (1H, td, J=1.7, 7.9 Hz, Ar—H), 7.05-7.11 (1H, td, J=1.7, 7.9 Hz, Ar—H), 7.19-7.30 (7H, m, Ar—H), 7.60 (1H, br s, Ar—H), 8.22-8.25 ppm (1H, dd, J=1.5, 8.0 Hz, Ar—H). LCMS: M+H, 409.44 HPLC: 98.66% (2.268 mins, isocratic 90% acetonitrile, 10% water at 1 ml/min).