Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:17]=1.O.[NH2:26][NH2:27]>CCO>[NH2:2][C:1]1[NH:27][N:26]=[C:7]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([N:16]3[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]3)=[CH:19][CH:20]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3n[nH]c(N)c3C(N)=O)cc2)cn1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-methyl-1-(4-aminophenyl)-1H-imidazole (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH:19]2[N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:4][CH2:3]1.[N:21]#CBr.O>C1C=CC=CC=1.C(OCC)C>[C:1]([N:2]1[CH2:3][CH2:4][N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]2[CH2:20]1)#[N:21]
Reactant: N#CBr
Reactant: CN1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: N#CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reaction time: 24 h

Procedure:
A solution of mianserin (5.2 g) in anhydrous benzene (20 ml) was added slowly to a stirred solution of cyanogen bromide (2.3 g) in anhydrous benzene (20 ml) in an atmosphere of nitrogen. After 24 hours, the mixture was diluted with diethyl ether (50 ml) and shaken with water (50 ml). The separated aqueous layer was back extracted with a mixture of benzene and ether (equal volumes of each, total 50 ml) and the combined organic layers dried over anhydrous potassium carbonate and then evaporated under reduced pressure. The residual solid was recrystallised from ethanol to give 2-cyanonormianserin as colourless needles m.p. 164°-166° C. This compound is outside general formula I, and was used as an intermediate only.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:12](CC)[CH2:13]N3C(=O)C4C(=CC=CC=4)C3=O)[CH:11]=2)[CH:2]=1.O.[NH2:28]N.[CH2:30](O)[CH3:31]>>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:30][CH2:31][NH2:28])[CH:11]=2)[CH:4]=1
Reactant: CCO
Reactant: NN
Reactant: CCC(CN1C(=O)c2ccccc2C1=O)n1cnc(-c2cccnc2)c1
Solvent: O
Product: NCCCCn1cnc(-c2cccnc2)c1

Procedure:
Using the procedure of Stage B of Example 1, 1.66 g of the product of Stage A and 0.46 ml of hydrazine hydrate in 30 ml of ethanol were reacted to obtain 936 mag of the desired product which was used as is for the synthesis.
Reaction SMILES: [C:1](=O)([O:3]C(C)(C)C)N.[NH2:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:25][NH2:26])=O.CN1CCCC1=O>O>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:17]=[C:16]2[N:26]([C:1](=[O:3])[NH:9][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:25]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: NNC(=O)c1ccco1
Reactant: N#Cc1cccnc1N
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2ncccc2c2nc(-c3ccco3)nn12
Yield: 53 %

Procedure:
A mixture of the tert-butyl carbamate of 2-amino-3-cyanopyridine (4.6 g), 2-furoylhydrazine (2.65 g) and 1-methyl-2-pyrrolidone (46 mL) is heated at 160° over 18 hr. It is cooled and diluted with water (369 mL) to afford 2-(2-furyl)pyrido-[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidin-5(6H)one in 53% yield. It is purified by tituration in hot methanol, which removes the soluble impurities, and melts above 360° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C:52]([CH3:54])([CH3:53])[CH3:55])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 294 mg of 1-[4-(thiazol-2-yI)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113.5 mg (0.60 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF at 0° C. and the mixture is stirred at room temperature for 16 hours. Ice-water and ethyl acetate are added; the aqueous phase is separated off and extracted with ethyl acetate. The organic phases are washed 2× with water and brine, dried (Na2 SO4) and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate) and crystallisation from ethyl acetate/ether/hexane yield the title compound: Anal. (C36H50 N6O7S (1.4% H2O)) calc. C 59.97, H 7.15, N 11.66, S 4.45: found C 59.99, H 7.18, N 11.35, S 4.59; TLC: Rf =0.51 (methylene chloride/THF 3:1); HPLC20-100 : tRet =15.2; FAB MS (M+H)+ =711.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>C(O)C.CCOCC.N1CCCCC1>[CH2:17]([O:16][C:10](=[O:15])[C:11]([C:12](=[O:13])[CH3:14])=[CH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=CCC1CCCCC1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCOC(=O)C(=CCC1CCCCC1)C(C)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution of the above cyclohexyl-acetaldehyde (1.04 g, 8.25 mmol) and ethyl acetoacetate (0.873 mL, 6.85 mmol) in 300 mL ethanol was stirred in an ice bath as piperidine (7.3 uL, 73 umol) in 380 uL ethanol was added. The mixture was stirred in the ice bath for 5 hours and placed in a refrigerator for 16 hours. The reaction mixture was diluted with 50 mL ether and extracted with saturated sodium chloride (3×30 mL containing 2 drops AcOH). The brine layers were back-extracted with ether (2×40 mL). The combined ether layers were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated to give 2-acetyl-4-cyclohexyl-but-2-enoic acid ethyl ester (1.79 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH2:13])=[O:6])#[N:2].C1C=CC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:34](O)=[O:35])[NH:31]2)=[CH:27][CH:26]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:34]([C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([Cl:24])[CH:33]=2)=[O:35])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1N
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-cyclohexanecarboxylic acid cyanomethyl-amide (6.4 g, 35.31 mmol) in DMF (70 ml), were added HOBT (5.25 g, 38.84 mmol), 6-chloro-2-indolecarboxylic acid (7.60 g, 38.84 mmol), N-methylmorpholine (19.4 ml, 176.45 mmol), and EDCI (7.45 g, 38.84 mmol) respectively at 0° C. The reaction was stirred at room temperature for 16 hours, then 1N HCl (500 ml) was added and the resulting cloudy solution was extracted with ethyl acetate (3×200 ml). The organic layer was filtered through a Celite pad, washed with 1N NaOH (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo yielding 6-chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide, (6.25 g, 49%).
Reaction SMILES: N.Cl.C[NH:4]C.[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1OC(C(O)=O)=CC=1>O1CCOCC1>[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33]([NH2:4])=[O:34])[N:32]=1
Reactant: CNC
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Agent: Cl
Agent: N
Agent: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Solvent: C1COCCO1
Product: NC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 13.1 and making non-critical variations using 4 M ammonia solution in dioxane to replace dimethylamine hydrochloride, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid to replace 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide was obtained (19%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.53 (d, J=10.2 Hz, 2H), 7.33-6.99 (m, 4H), 6.54 (s, 1H), 6.38 (s, 1H), 5.22-5.01 (m, 2H), 4.75 (ABq, 2H), 4.46 (t, J=8.8 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.3, 161.9, 161.6, 160.9, 159.2, 143.2, 142.2, 136.8, 132.5, 129.2, 124.1, 123.8, 120.8, 120.4, 119.7, 109.6, 92.8, 80.0, 72.5, 57.3, 37.4, 28.7; MS (ES+) m/z 403.8 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=[O:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.[OH-].[Na+]>[ClH:27].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[CH2:11][CH:10]3[N:5]([CH2:6][CH2:7][C:8]4[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=43)[CH2:4][CH2:3]2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)c3ccc(F)cc3)CCN1CC2
Product: Cl
Reaction time: 1 h
Yield: 21 %

Procedure:
To a cold mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine, (7 g, 0.026 mole) in 200 ml of toluene and 50 ml of 20% NaOH, was added dropwise 4.5 g of 4-fluorobenzoyl chloride. The mixture was stirred in the cold for 1 hour and at room temperature for 1 hour. The resulting solid product was collected and chromatographed over silica gel using ethyl acetate-methanol-chloroform (3:1:1) as eluant. The major fraction (5.0 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and ether, isolated by removal of the solvent and recrystallized from methanol-ether to yield 2.3 g of the desired product, m.p. (decomposed at 257°-8°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR29##
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]2[O:16][CH2:15][CH:14]([CH2:17][OH:18])[O:13][C:10]2=[N:11][CH:12]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][CH:14]1[O:13][C:10]2=[N:11][CH:12]=[C:7]([CH3:6])[CH:8]=[C:9]2[O:16][CH2:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc2c(c1)OCC(CO)O2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)OCC(COS(C)(=O)=O)O2
Temperature: 0 °C
Yield: 99 %

Procedure:
Methanesulfonyl chloride (0.00103 mol) was added to a mixture of intermediate (39) (0.00081 mol) and triethylamine (0.0019 mol) in DCM, stirred at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. Water was added. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 0.208 g of 2,3-dihydro-7-methyl-[1,4]dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate (40).
Reaction SMILES: [C:1]([OH:9])(=O)[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.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
From benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35].C[OH:38]>C1COCC1>[CH2:27]([O:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:34]([C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)=[O:35])[C:7]2=[O:38])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:28]
Reactant: CO
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)c4ccco4)c3C2=O)ccc1OC
Yield: 37 %

Procedure:
A solution of (1S)-7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (0.85 g, 2.0 mmol) and 2-furoyl chloride (0.40 mL, 4.1 mmol) in THF (5 mL) was heated to reflux for 17 hours. To the mixture was added methanol (4 mL). The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silica Gel, EtOAc/hexane) to give (1S)-Furan-2-carboxylic acid {2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a solid (380 mg, 37% yield): mp 184-186° C.; 1H NMR (CDCl3) δ 1.45 (t, J=7 Hz, 3H, CH3), 2.86 (s, 3H, CH3), 3.76-3.80 (m, 1H, CHH), 3.83 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 4.56 (dd, J=10, 14 Hz, 1H, CHH), 5.90 (dd, J=5, 10 Hz, 1H, NCH), 6.57-6.58 (m, 1H, Ar), 6.81-6.84 (m, 1H, Ar), 7.10-7.13 (m, 2H, Ar), 7.27-7.28 (m, 1H, Ar), 7.47-7.50 (m, 1H, Ar), 7.63-7.69 (m, 2H, Ar), 8.84 (d, J=9 Hz, 1H, Ar), 10.39 (s, 1H, NH); 13C NMR (CDCl3) δ 14.70, 41.65, 48.74, 54.68, 55.95, 60.37, 64.55, 111.51, 112.51, 112.75, 115.76, 116.47, 118.42, 120.42, 125.03, 129.34, 131.26, 136.15, 137.25, 145.40, 147.05, 148.63, 149.75, 156.49, 167.51, 169.39. Analy, calculated for C25H24N2O8S: C, 58.59; H, 4.72; N, 5.47. Found: C, 58.34; H, 4.86; N, 5.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].C(OC1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: CC(C)Oc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was treated with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (prepared from 4-isopropoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-{7-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-{7-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzo[b]thiophen-4-yl}-propionic acid as colorless solid.
Reaction SMILES: C1CCC(=C(F)CNCC2C=CC([F:15])=CC=2)CC1.[C:19]([C:21]1[CH:22]=[C:23]([N:27]=[N+]=[N-])[CH:24]=[CH:25][CH:26]=1)#[N:20].F>CCCCCC.CCOCC>[C:19]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[F:15])[NH2:27])#[N:20]
Reactant: FC(CNCc1ccc(F)cc1)=C1CCCCC1
Reactant: N#Cc1cccc(N=[N+]=[N-])c1
Agent: F
Solvent: CCOCC
Solvent: CCCCCC
Product: N#Cc1cc(N)ccc1F
Temperature: 0 °C

Procedure:
A 50 ml. ether and hexane solution of 9.8g. of 3-cyanophenylazide prepared in Step A above was charged to a rocker bomb and the ether and hexane were blown down under nitrogen. Then, 100 ml. of hexane was introduced, followed by 20 ml. of concentrated hydrogen fluoride, after which the bomb was shaken at room temperature for 10 hours. The reaction mixture was cooled, vented, and poured from the bomb, and the bomb rinsed with 40 ml. of water and 40 ml. of dichloromethane. The combined hexane, dichloromethane, and hydrogen fluoride were blown down under nitrogen. The resulting residue was combined with the aqueous rinse, cooled to 0° C., and rendered alkaline with KHCO3. The residue was then extracted three times with 75 ml. of dichloromethane per extraction, and the combined extracts dried over MgSO4 and then concentrated under reduced pressure to yield 6.5g. of a brown solid. This product was then recrystallized from boiling cyclohexane to yield 5.8g. (53%) of product with a m.p. of 88°-89° C. whose structure was confirmed by IR.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
Powdered aluminum chloride (270 g., 2 moles) is added slowly at 0° C. to a stirred mixture of 2,3-dichloroanisole (177 g., 1.0 mole) and succinic anhydride (100 g., 1.0 mole) in methylene chloride (800 ml.). The mixture then is stirred at 0° C. for two hours, then at 20°-25° C. for 16 hours and then refluxed for one hour and poured into ice cold 1 N HCl (2.4 l.). The aqueous mixture is heated to 65° C. and allowed to cool to 20° C. The sticky solid that separates is triturated with warm butyl chloride to obtain 136 g. product, melting point 140°-145° C. After crystallization from ethanol-water (5:7) there is obtained 3-(2,3-dichloro-4-methoxybenzoyl)propionic acid (125 g.), melting point 142°-144° C..
Reaction SMILES: OCC(CO)(CO)CO.N1C=CC=CC=1.CN(C=O)C.[CH3:21][CH:22]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:23][CH2:24][CH2:25][C:26](OC[C@@H]([C@@H](CO)O)O)=[O:27].C(Cl)[Cl:53]>>[CH3:21][CH:22]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:23][CH2:24][CH2:25][C:26]([Cl:53])=[O:27]
Reactant: ClCCl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)OC[C@H](O)[C@H](O)CO
Agent: OCC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)Cl
Temperature: 25 °C

Procedure:
Pentaerythritol (3.81 g), 2.21 g of pyridine, and 120 ml of dry DMF were mixed and dissolved with heating. The product was cooled to room temperature, the solution of 5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride obtained in the step of synthesis of 1-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol [formula (7)] in 5 ml of methylene chloride was added dropwise thereto, and the mixture was then agitated at room temperature for 1 hour. 100 ml of Methylene chloride was added to the resulting reaction solution, the mixture was washed 3 times with saturated saline, and dried over anhydrous sodium sulfate. Following filtration and concentration under reduced pressure, the concentrate was purified by silica gel column chromatography to obtain 2.50 g of mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol having the following properties. The purity determined by HPLC analysis was not lower than 99.5%. The results of NMR analysis are as shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:16][C:15]2[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:13][C:12]([CH3:23])=[N:11][C:10]=2[CH:9]=1)=[O:7].[NH:24]1[C:32]2[C:27](=C[CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:23]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:15]4[S:16][C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])=[CH:9][C:10]=4[N:11]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cc2ccccc2[nH]1
Reactant: COCCNC(=O)c1cc2nc(C)nc(N3CCOCC3)c2s1
Product: COCCNC(=O)c1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1

Procedure:
2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2-methoxyethyl)-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 189. NMR: 400 MHz; CDCl3 3.44 (3H, s); 3.60 (2H, m); 3.70 (2H, m); 3.92 (4H, t, J=4.8 Hz); 4.15 (4H, t, J=4.8 Hz); 6.74 (1H, br t); 7.30 (1H, d, J=7.8 Hz); 7.35 (1H, m); 7.52 (1H, d, J=8.0 Hz); 7.57 (1H, s); 7.82 (1H, s); 8.20 (1H, d, J=7.4 Hz); 8.30 (1H, br s). MS: (ESI+) M+H (438)
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:19])[CH:13]=1.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=1>C1COCC1>[ClH:19].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=2)=[C:14]([Cl:19])[CH:13]=1
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (261 mL of a 1 M solution in hexanes) was added dropwise over 30 minutes to a solution of 4-bromo-2-chlorophenylamine (35.0 g, 172 mmol) in THF (80 mL) at −78° C. After 1 hour, 4,6-dichloronicotinic acid (23) (15.7 g, 81.7 mmol) was added dropwise over 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred 16 hours. The reaction mixture was quenched with water, diluted with EtOAc and acidified with 1 N HCl. The resulting precipitate was isolated by filtration and washed with EtOAc. The solids were twice concentrated from toluene, triturated with CH2Cl2 and collected by filtration. The solids were further concentrated from toluene (3×) followed by drying in vacuo to give the desired product (24) containing a small amount of water (36.0 g).