Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:58])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:18][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][C:15]=2[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[CH:6][C:5]=1[OH:57].[OH-].[Na+].Cl>CCO.O>[OH:57][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:55])[F:56])[CH:48]=3)=[CH:16][C:17]([C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:58])=[O:2]
Reactant: COC(=O)c1ccc(OCCOc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 2-hydroxy-4-{2-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl[1,1′:3′,1″]terphenyl-2′-yloxy]-ethoxy}-benzoic acid methyl ester (0.980 g, 1.21 mmol, 1 eq) in EtOH (20 mL) was added 50% NaOH (10 mL) and the reaction was heated at reflux overnight. It was cooled to rt, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford the title compound (0.92 g, 96%) as a white foam. 1H NMR (DMSO-d6) δ 13.60 (bs, 1H); 11.40 (bs, 1H); 8.59 (bt, 1H); 8.00–7.92 (m, 6H); 7.74–7.65 (m, 4H); 7.56 (d, 1H); 7.25–7.10 (m, 5H); 6.08–6.00 (m, 2H); 3.66 (bd, 2H); 3.52 (bd, 2H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.27 (m, 8H); IR (KBr) 3350, 2950, 2850, 1670, 1620, 1550, 1500, 1460, 1320, 1230, 1220, 1160, 1120, 1095, cm−1; mass spectrum [(−)APCI], m/z 792 (M−H)−; Anal. Calcd. for C44H41F6NO6: C, 66.58; H, 5.21; N, 1.76. Found: C, 64.86; H, 5.22; N, 1.68.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[C:21](O)=[CH:22][C:23]3[O:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]=3[CH:30]=1)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:18][O:19][C:21]3[CH:22]=[C:23]4[C:24](=[CH:30][C:20]1=3)[CH2:25][C:26]([CH3:29])([CH3:28])[O:27]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CC(C)(C)O4)c2c(Br)cccc21
Yield: 52 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using ethyl [4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 52% yield: 1H NMR (300 MHz, CDCl3) δ 7.22-7.10 (m, 2H), 6.70 (d, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 5.0 (d, 1H); 4.86 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.28-4.18 (m, 2H), 2.79 (s, 2H), 1.43 (s, 3H); 1.39 (s, 3H), 1.28 (t, 3H); MS (ES+) m/z 472.5 (M+1), 474.5 (M+1).
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])(=[O:17])=[O:16])[C:10]2=[O:29])[CH:4]=1)#[N:2].C(C1SC=C(CN2CC[C@H](NS([C:47]3[CH:56]=[CH:55][C:54]4[C:49](=[CH:50]C(OC)=CC=4)[CH:48]=3)(=O)=O)C2=O)C=1)#N.C(Br)C1C=CC=CC=1>>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:50][C:49]3[CH:54]=[CH:55][CH:56]=[CH:47][CH:48]=3)[S:15]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[C:19]=3[CH3:28])(=[O:17])=[O:16])[C:10]2=[O:29])[CH:4]=1)#[N:2]
Reactant: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3csc(C#N)c3)C2=O)sc2ccc(Cl)cc12
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Agent: BrCc1ccccc1
Product: Cc1c(S(=O)(=O)N(Cc2ccccc2)[C@H]2CCN(Cc3csc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as in EXAMPLE 129, Part A, in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide in place of MeI. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)O)cc2)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)C1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][OH:33].CC(C)([O-])C.[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18]([O:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(F)c(F)c1
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(OCc2ccccn2)c(F)c1
Temperature: 180 °C
Yield: 23 %

Procedure:
A mixture of N-{5 -[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5 -trifluorobenzamide (100 mg, 0.29 mmol), 2-pyridinylmethanol (400 μl) and potassium t-butoxide (32 mg, 0.29 mmol) in NMP (600 μl) was heated in the microwave at 180° C. for 1.51 hrs. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with dilute aqueous citric acid. Evaporation of the ethyl acetate gave impure product which was purified on silica column chromatography eluting with 0 to 100% ethyl acetate in isohexane. The solvents were evaporated to give a residue which was dissolved in ethyl acetate, then extracted with dilute hydrochloric acid. The aqueous extracts were basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate to give the title compound as a solid (29 mg, 23%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.36 (s, 2H), 7.37 (m, 2H), 7.64 (m, 2H), 7.84 (m, 4H), 8.40 (m, 1H), 8.56 (m, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 436.
Reaction SMILES: [O:1]1CCC[CH2:2]1.[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33]Br.CO.C[O-].[Na+]>O>[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33][O:1][CH3:2]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 4 ml of tetrahydrofuran solution containing 459 mg (0.81 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added 4 ml of 28% sodium methoxide methanol solution, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 359 mg of the title compound as a colorless oil. (Yield: 86%)
Reaction SMILES: [CH2:1]([S:4]([O:7][CH2:8][CH2:9][N:10]([CH3:17])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3].N1CC[CH2:20][C@@H:19]1CO>>[CH2:14]([S:11]([N:10]1[CH2:17][CH2:20][CH2:19][C@@H:9]1[CH2:8][O:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:13])=[O:12])[CH2:15][CH3:16]
Reactant: CCCS(=O)(=O)OCCN(C)S(=O)(=O)CCC
Reactant: OC[C@H]1CCCN1
Product: CCCS(=O)(=O)OC[C@H]1CCCN1S(=O)(=O)CCC

Procedure:
Prepared as described for 2-(N-methylpropylsulfonamido)ethyl propane-1-sulfonate (example 76, step 1 using (R)-1-pyrrolidin-2-yl-methanol instead of 2-(methylamino)ethanol.
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:68]=[CH:67][C:66](B(O)O)=[CH:65][CH:64]=1>>[CH3:33][S:30]([N:27]1[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=4)=[C:2]([C:66]4[CH:67]=[CH:68][C:63]([C:62]([F:73])([F:72])[F:61])=[CH:64][CH:65]=4)[C:3]3=[O:34])=[CH:8][CH:7]=2)[CH2:29][CH2:28]1)(=[O:31])=[O:32]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(C(F)(F)F)cc2)=C3c2ccc(C(F)(F)F)cc2)CC1
Yield: 21 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-3-[4-(trifluoromethyl)phenyl]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (21%).
Reaction SMILES: C1(COC(=O)[NH:10][C@H:11]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1>C(O)C>[CH3:27][C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][C@@H:11]([NH2:10])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Reaction time: 48 h
Yield: 116 %

Procedure:
A mixture of (S)-[1-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-2-phenylethyl]carbamic acid phenylmethyl ester (2.89 g, 7.51 mmol) and 10% Pd--C (0.171 g) in ethanol (70 ml) was stirred under hydrogen for 2 days. The reaction mixture was filtered through celite and the filtrate was evaporated to leave the title compound (2.18 g) as a solid, nmr(δ,CDCl3) includes 1.43(s,9H), 2.5-2.62 and 2.83(m and dd,2H), 3.0 and 3.1-3.25(m,2H), 3.25-3.4(m,1H), 5.0-5.15(m,1H), 7.15-7.35(m,5H).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].II.Cl>CCOCC.[Zn]>[CH3:1][C:2]1[CH:3]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)CBr
Reactant: CSc1ccc(CC2c3ccccc3C(=O)C2C)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: CCOCC
Product: COC(=O)CC1C(C)=C(Cc2ccc(SC)cc2)c2ccccc21
Temperature: 0 °C

Procedure:
To a solution of the indanone derivative from Step 1 (885 mg, 3.14 mmol) in ether (20 mL) were added successively zinc (840 mg, 12.8 mmol), methyl bromoacetate (0.5 mL, 5 mmol) and iodine (200 mg). The reaction mixture was refluxed for 3 hours, then cooled to 0° C. and 6N aqueous HCl was added dropwise until the zinc complex was completely decomposed. The organic layer was decanted, washed with brine, dried over Na2SO4 and evaporated to dryness. The oily residue was dissolved in formic acid and evaporated to dryness to complete the dehydration of the intermediate methyl [1-hydroxy-2-methyl-3-(4-methylthiobenzyl)indan-1-yl]acetate. The resulting oily residue was chromatographed on silica gel eluting with a 1:19 mixture of ethyl acetate-hexane to afford pure title compound as an oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[CH3:21][S:22][C:23]1[NH:27][C:26](=[S:28])[S:25][N:24]=1>>[CH3:21][S:22][C:23]1[N:27]([CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:26](=[S:28])[S:25][N:24]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: CSc1nsc(=S)[nH]1
Agent: Cl
Product: CSc1nsc(=S)n1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 92 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 3-(methylthio)-1,2,4-thiadiazole-5(4H)-thione. m/e+ 399 for C19H19N4S3 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.67 (d, J=7.7 Hz, 2H), 7.57 (d, J=9.1 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.11 (d, J=9.1 Hz, 1H), 5.04 (s, 2H), 2.67 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 186.346, 171.423, 145.801, 144.701, 138.203, 130.870, 129.680, 128.573, 128.300, 122.825, 121.733, 117.047, 111.982, 29.739, 21.444, 18.577, 14.968, ppm.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:21][C:10]1[C:11](=[O:14])[NH:12][CH:13]=[C:8]([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cc(C(c2ccccc2)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.3 %

Procedure:
A mixture of 5-(diphenylmethyl)pyridin-2(1H)-one (0.3 g) and N-chlorosuccinimide(0.184 g) in DMF (3 mL) was stirred at ambient temperature for 23 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution and the resulting precipitates were collected by filtration and washed with water to afford 3-chloro-5-(diphenylmethyl)pyridin-2(1H)-one (0.31 g) as white powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:27][CH:28]=2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(-c4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (62 μL, 0.45 mmol) in methylene chloride (20 mL) was added dropwise 4-biphenylcarbonyl chloride (89 mg, 0.41 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2.5) as the eluent. Yield: 100 mg (59%) of the title compound as white crystals: mp 232-233° C.; EIMS (70 eV) m/z (relative intensity) 425 (11, M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:16])[CH:4]=1.C1C(=O)N([Br:24])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)Cl>CC#N.O>[Br:24][CH2:16][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1CBr
Temperature: 70 °C

Procedure:
A mixture of methyl 4-methoxy-2-methyl-5-nitrobenzoate (994 mg, 4.41 mmol) and NBS (943 mg, 5.3 mmol) in MeCN (20 mL) was degassed and then AIBN (15 mg, 0.09 mmol) was added. The mixture was heated to 70° C. for 18 h. Further AIBN (15 mg, 0.09 mmol) was added and the mixture was heated to 70° C. for 24 h. Further AIBN (15 mg, 0.09 mmol) and NBS (300 mg, 1.7 mmol) were added and the mixture heated to 70° C. for 24 h. Further AIBN (15 mg, 0.09 mmol) was added and the mixture was heated to 70° C. for 24 h. DCM (50 mL) and water (50 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo to give crude methyl 2-(bromomethyl)-4-methoxy-5-nitrobenzoate that was used directly in the next reaction without any purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[CH:3]=1>C1COCC1.CO>[CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2COc3c(C)c(C)cc(C)c32)cc1
Yield: 81 %

Procedure:
Using 4,6,7-trimethyl-3-(4-methylphenyl)-1-benzofuran obtained in Reference Example 191, the title compound was synthesized in the same manner as in Reference Example 144. Yield 81%. Melting point: 65-66° C. (THF-methanol).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([F:14])[CH:16]=2)=[O:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCc1ccc(C(=O)O)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)Oc2ccc(C#N)c(F)c2)nc1
Reaction time: 3 h
Yield: 10 %

Procedure:
5-n-butyl picolinic acid (1.8 g) and 3-fluoro-4-cyanophenol (1.4 g) were dissolved in methylene chloride (30 ml). While the resulting solution was kept at 0° C. or lower, a solution (20 ml) of dicyclohexylcarbodimide (2.1 g) in methylene chloride was dropped to the above solution, followed by further agitating for 3 hours, filtering off the resulting solids, adding 2N-NaOH aqueous solution to the filtrate, separating the methylene chloride layer, washing it with water till the washing water became neutral, distilling off the solvent from the methylene chloride layer and recrystallizing the residue from ethanol to obtain the objective 3-fluoro-4cyanophenyl 5-n-butylpicolinate (0.3 g) having a m.p. of 45.1°-46.1° C.
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]([CH3:11])=[O:10])=[CH:5]OCC)=[O:3].[NH2:12][C:13]1[C:14]([Cl:23])=[C:15]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17]>CCOCC>[CH3:11][C:9]([C:4]([C:2]([CH3:1])=[O:3])=[CH:5][NH:12][C:13]1[C:14]([Cl:23])=[C:15]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:10]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Solvent: CCOCC
Product: CC(=O)C(=CNc1cc(Cl)cc(C(=O)O)c1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
9.35 g (0.06 mole) of methyl 1-methylcarbonyl-2-ethoxyvinyl ketone were added dropwise to a suspension of 10.3 g (0.05 mole) of 3-amino-2,5-dichlorobenzoic acid in 40 ml of ether. The mixture was stirred for a further 5 hours at room temperature and the precipitate was then filtered off and washed with acetonitrile. 12 g (76% of theory) of 3-[2,2-bis-(methylcarbonyl)-vinylamino]-2,5-dichlorobenzoic acid were obtained in the form of colourless crystals of melting point 244°-246° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.O>CC(N(C)C)=O>[NH2:30][C:22]1[N:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:21]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 90 °C

Procedure:
322 mg (1.38 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 50 mg (2.1 mmol) NaH is added. 136 mg (0.69 mmol) 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine 24 is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate: cyclohexane from 1:1 to 3:1).