Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN1CCCC1=O.Cl[C:16]1[N:17]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1)[N:19]=2.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C(N(CC)CC)C>[CH2:38]([N:17]1[C:16]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:3][CH2:2]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1)=[N:21][C:22]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH:39]([CH3:41])[CH3:40]
Reactant: C1CNCCNC1
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
Homopiperazine (130 mg, 1.3 mmol) and N-methylpyrrolidone (1 ml) were added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture stirred at 120° C. for 2 hours. The reaction mixture was cooled and partitioned with methylene chloride and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Triethylamine (110 μl) and mesyl chloride (45 μl, 0.58 mmol) were added to the resulting mixture and the resulting mixture was stirred for 0.5 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (153 mg, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]([CH3:55])[C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][NH2:51]>CN(C=O)C>[CH3:45][N:46]([CH3:55])[C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][NH:51][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CN(C)c1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(N(C)C)c4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 3-dimethylaminobenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(3-dimethylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.11 min, MH+ 427.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37].O>C1COCC1>[C:36]([O:25][CH2:24][CH2:23][C:21]1[NH:20][C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH:22]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-c2nc3cc(CCO)[nH]c3nc2-c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethanol (step 2) (73 mg, 0.213 mmol) in dry THF (2 ml) at RT was treated with DIPEA (0.082 ml, 0.468 mmol) and acetyl chloride (0.018 ml, 0.255 mmol). After stirring for 16 hours at RT, the mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound, 2-(2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([NH:19]N)=[C:8]3[C:16](=[O:17])[NH:15][NH:14][C:13](=[O:18])[C:9]3=[N:10][C:11]=2[CH:12]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27]N)[CH3:23]>N1C=CC=CC=1.O>[CH2:22]([O:24][C:25]([CH2:26][CH2:27][NH:19][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:12][C:11]=2[N:10]=[C:9]2[C:13](=[O:18])[NH:14][NH:15][C:16](=[O:17])[C:8]=12)=[O:29])[CH3:23]
Reactant: NNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Yield: 11.3 %

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydrazinopyridazino[4,5-b]-quinoline-1,4-dione hydrochloride (1.0 g, 2.9 mM, as prepared in Example 44) and beta alanine ethyl ester hydrochloride (49.0 g, 320 mM) in pyridine (52 mL) was refluxed for 23 hr. After cooling, the vigorously stirred reaction mixture was diluted slowly with water (100mL) and then filtered to separate a fine red solid. The collected solids were washed with water and chromatographed (eluant: methanol/methylene chloride; 5/95) over silica gel to provide the title ester (0.13 g, 13%) as a red powder, mp 258°-260° C.; MS(CI): 363 (M+H).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[CH3:7][NH+:8]1[CH:13]([CH3:14])[CH2:12][CH:11]=[C:10]([C:15]([O:17]CC)=O)[CH2:9]1.[CH3:20][NH+:21]1[CH:26]([CH3:27])[CH2:25][CH:24]=[C:23]([C:28]([O:30]CC)=O)[CH2:22]1.[C:33](=[N:36]O)([NH2:35])[CH3:34].Br.[CH:39]([C:42](=[N:44]O)[NH2:43])(C)C>>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[CH3:7][NH+:8]1[CH:13]([CH3:14])[CH2:12][CH:11]=[C:10]([C:15]2[O:17][N:36]=[C:33]([CH3:34])[N:35]=2)[CH2:9]1.[CH3:20][NH+:21]1[CH:26]([CH3:27])[CH2:25][CH:24]=[C:23]([C:28]2[O:30][N:44]=[C:42]([CH3:39])[N:43]=2)[CH2:22]1
Reactant: CC(N)=NO
Reactant: CCOC(=O)C1=CCC(C)[NH+](C)C1
Reactant: CC(C)C(N)=NO
Agent: Br
Agent: O=C([O-])C(=O)[O-]
Product: Cc1noc(C2=CCC(C)[NH+](C)C2)n1

Procedure:
The compound was synthesized as described in Example 17 using 1,6-dimethyl-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridinium oxalate (Bishop, Z. Naturforsch. 25b, 1249-1251 (1970)) and acetamide oxime instead of arecoline, HBr and isopropylcarboxamide oxime, respectivelY. M.P. 115°-117° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: CC(=O)Cc1ccnc(Cl)c1
Product: CC(=O)Cc1ccnc(N2CCOCC2)c1

Procedure:
A stirred solution of 1-(2-chloro-pyridin-4-yl)-propan-2-one (1.6 g, 9.47 mmol) in morpholine is heated to 105° C. for 3 days. The morpholine is removed in vacuo to yield the crude product. Purification by chromatography on silica, eluting with 1:1 ethyl acetate-hexane affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:16])[N:3]=1.[CH2:17]([O:19][C:20]1[CH:25]=[C:24]([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][N:27]=2)[CH:23]=[CH:22][C:21]=1[NH:32]C=O)[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:32][C:21]3[CH:22]=[CH:23][C:24]([C:26]4[N:30]([CH3:31])[CH:29]=[N:28][N:27]=4)=[CH:25][C:20]=3[O:19][CH2:17][CH3:18])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1cc2cnc(S(C)(=O)=O)nc2c(Cl)n1
Reactant: CCOc1cc(-c2nncn2C)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(-c2nncn2C)ccc1Nc1ncc2cc(C)nc(Cl)c2n1
Temperature: 120 °C
Yield: 27.2 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 178, 31 mg, 0.120 mmol) in DMSO (5 mL) was added N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 150, 35.5 mg, 0.144 mmol) and Cs2CO3 (78 mg, 0.241 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexanes followed by elution through an SCX-2 column using MeOH—1M NH3 in MeOH to afford the title compound (12.9 mg, 27%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]1[C:15](OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[CH2:24][CH2:25][N:26]1[C:34]([O:35]C)=[N:33][C:32]2[C:27]1=[N:28][C:29]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=2[NH2:37].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]1[CH:15]([CH2:8][CH2:1][CH2:2][CH3:3])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[NH:33][C:32]2[C:27]1=[N:28][C:29]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[N:30][C:31]=2[NH2:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Reactant: CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC(CCCC)N3CCN(C)CC3Cc3ccccc3)c2n1

Procedure:
The compound obtained in Step (iii) was reacted with the compound obtained in Example 1, Step (i) in the presence of potassium iodide (166 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in DMF to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10]C(C1C=NC=CC=1)=O)=[O:6].C[I:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[I-:22].[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10][C:27]([CH:26]1[CH2+:25]=[CH:24][CH:2]=[CH:3][N:4]1[CH3:5])=[O:23])=[O:6]
Reactant: O=NN(CCCl)C(=O)NCCOC(=O)c1cccnc1
Reactant: C1CCOC1
Reactant: CI
Product: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCCl)N=O
Product: [I-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 122 (1.5 g, 5 mmol) in 40 mL of tetrahydrofuran was treated with excess methyl iodide. The mixture was stirred at 50° C. for 4 hours. The finely crystalline, yellow solid thus obtained (1.8 g, 82%) melted at 120°-121° C. and had the structure ##STR151## as confirmed by elemental analysis.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3([C:17](=[S:20])[NH:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]3=O)[CH:7]=[CH:6][C:5]=12.[C:21]1([S:31]([NH:34][CH:35](N)[CH3:36])(=[O:33])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.[NH3:38]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:21]1([S:31]([NH:34][CH2:35][CH2:36][NH:38][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]2([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)[C:17](=[S:20])[NH:18][CH3:19])(=[O:33])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: CC(N)NS(=O)(=O)c1cccc2ccccc12
Reactant: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1NCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
600 m of 1-(imidazo[1,2-a]pyridin-6-yl)-N-methyl-2-oxocyclohexanecarbothioamide and 2.09 g of 1-naphthalenesulfonylaminoethylamine were dissolved in 20 ml of dichloromethane to form a solution. 2 ml of a 1 M solution of titanium tetrachloride in dichloromethane was added to this solution in 30 minutes at room temperature. The obtained mixture was stirred overnight, followed by the addition of 1 ml of concentrated aqueous ammonia. The crystal thus precipitated was filtered out, followed by the washing with 10% methanol/dichloromethane. The filtrate was concentrated in a vacuum, followed by the addition of ml of methanol. 200 mg of sodium cyanoborohydride was added to the mixture at room temperature. The obtained mixture was stirred for one hour and concentrate, in a vacuum, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with chloroform. The chloroform phase was dried over anhydrous sodium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (solvent: a 10:10:1 dichloromethane/ethyl acetate/methanol mixture) to give 280 mg of a lower-polarity diastereomer (L-form) and 850 mg of a higher-polarity diastereomer (M-form) each as a pale-yellow crystal.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C:22](=[O:31])[O:21]1.[NH4+].[Cl-]>C(OCC)C.C1COCC1.O>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C:22]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)([OH:31])[O:21]1
Reactant: Brc1nccs1
Reactant: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)C(O)(c1nccs1)OC2=Cc1c(Cl)cncc1Cl
Temperature: -80 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
A milky solution of 2-bromothiazole (5.6 g, 34.2 mmoles) in dry ethyl ether (17 ml) was added dropwise to a solution of n-butyl lithium (14.4 ml, 36 mmoles) in dry ethyl ether (50 ml), under N2 at −80° C. The reaction mixture was stirred at −80° C. for 15 minutes, then a solution of 3-(3,5-dichloro-pyridin-4-ylmethylene)-6-methoxy-3H-isobenzofuran-1-one (10 g, 31 mmoles), prepared as described in example 37, in dry THF (60 ml) was slowly added. After 45 minutes at −78° C., the resultant solution was treated with saturated NH4Cl, with water and brought to room temperature. The aqueous phase was separated and extracted with ethyl acetate, decoloured with charcoal, filtered over celite and concentrated under vacuum. The resultant foam was flash cromatographed (eluent petrolatum:ethyl acetate 6:4) obtaining 4.64 g of the title compound (yield: 38%).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C([N:47](CC)[C:48]([CH2:50]P(=O)([O-])[O-])=[O:49])C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[C:34]1([C:32]([C:31]2[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=2)=[CH:50][C:48]([NH2:47])=[O:49])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCN(CC)C(=O)CP(=O)([O-])[O-]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC(N)=O)c2ccccc2)ccc1OC

Procedure:
The acrylamide was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (0.3 g, 1.2 mmol), diethylcarbamoylmethylphosphonate (0.25 g, 1.3 mmol) and lithium hexamethyldisilazide (1 mL, 1.3 mmol, 1.3 M) with a reaction time of 54 hours at reflux. The crude mixture was purified by flash column chromatography (silica gel, 45% ethyl acetate/methylene chloride) to afford 0.06 g (17%) of a mixture of the E and Z isomers as an oil: 1H NMR (CDCl3) δ 7.54-7.19 (m, 10 H), 7.00-6.65 (m, 6 H), 6.34 (s, 2 H), 5.54 (s, 1 H), 5.55 (s, 1 H), 5.24 (s, 1 H), 5.04 (s, 1 H), 4.16 (m, 4 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 1.60-1.33 (m, 6 H); 13C NMR (CDCl3) δ 168.7, 168.6, 150.8, 150.4, 149.7, 148.4, 148.0, 140.7, 138.2, 133.0, 130.2, 129.2, 129.1, 128.8, 128.3, 128.0, 121.9, 121.6, 120.0, 113.7, 111.9, 111.4, 110.8, 64.4, 64.3, 55.9, 14.6; Anal. Calcd for C18H19NO3.0.35H2O. Theoretical: C, 71.19; H, 6.54; N, 4.61. Found: C, 71.19; H, 6.68; N, 4.45.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[C:15](Cl)(=[O:17])[CH3:16]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Aluminum trichloride (846 mg) was added to a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg) in dichloromethane (5 ml) at room temperature over 10 minutes. Subsequently, acetyl chloride (135 μl) was added and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice-cold water and separated by adding dichloromethane. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (186 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH:29]([O:31][CH3:32])[CH2:28][CH:27]5[C:33](C)(C)[O:34][SiH2]C(C)(C)C)=[O:25])[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:42])=[O:4].C(O)(C(F)(F)F)=O>C(O)(=O)C.C1COCC1>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]([N:26]5[CH2:30][CH:29]([O:31][CH3:32])[CH2:28][CH:27]5[CH2:33][OH:34])=[O:25])[S:23][C:16]=34)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:42])=[O:4]
Reactant: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CC(OC)CC5C(C)(C)O[SiH2]C(C)(C)C)sc34)ccc21
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CC(OC)CC5CO)sc34)ccc21

Procedure:
Example 3(o) was prepared by dissolving the starting material 5-{2-[2-(tert -Butyl-dimethyl-silanyloxymethyl)-4-methoxy-pyrrolidine-1-carbonyl]-thieno[3,2-b]pyridin-7-yloxy}-2-methyl-indole-1-carboxylic acid methylamide (0.55 g, 1.00 mmol), as prepared in step i below, in 1 mL of acetic acid in 0.5 mL of THF and 0.5 mL of TFA and stirring at 50° C. for 3 h. The reaction mixture was quenched with 5 mL of sat. NaHCO3 and 50 mL of EtOAc the partitioned with 50/50 NaHCO3 (2×50 mL) organic layer dried over NaSO4 and concentrated. The residue purified with a 2 mm choromatotron rotor eluting with EtOAc/CH2Cl2/MeOH (2:1:0.2) then combining purified fractions. The product was then crashing out of EtOAc and diethyl ether producing 0.34 g (68.5%) of 5-[2-(2-Hydroxymethyl-4-methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-indole-1-carboxylic acid methylamide as white solid. HPLC: Rt 5.06 min. (94% area). 1H NMR (CDCl3, 400 MHz) δ: 8.50 (1H, d, J=5.3 Hz), 7.81 (1H, s), 7.71 (1H, d, J=9.0), 7.30 (1H, s), 7.03 (1H, d, J=6.9 Hz), 6.60 (1H, d, J=5.3 Hz), 6.33 (1H, s), 5.69 (1H, bs), 4.57 (1H, q, J=6.8 Hz), 4.33 (1H, s), 4.08 (1H, d, J=11.6 Hz), 4.00 (1H, s), 3.86 (2H, t, J=11.6 Hz), 3.85-3.75 (1H, m), 3.28 (3H, d, J=4.3 Hz), 2.61 (3H, s), 2.34-2.29 (1H, m). HRMS (ESI) C25H27N4O5S2 (M+H+) m/z: Calc. 495.1702, Found: 495.1704. Anal. (C25H26N4O5S2.0.2 EtOAc) Calc'd: C, 60.50; H, 5.43; N, 10.94; Found: C, 60.73; H, 5.61; N, 10.10.86.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)C(=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:17]#N.[CH:19]([NH2:21])=O>>[NH2:17][C:13]1[C:14]2[C:5]([C:19]([NH2:21])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: N#N
Reactant: NC=O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: Nc1c2ccccc2c(N)c2ccccc12

Procedure:
20 g of anthraquinone was heated at boiling point with 200 ml formamide for 4 hours. The supernatent anthraquinone slowly disappeared while yellow crystals deposited. The solution was cooled, suction filtered and washed thoroughly with alcohol. The resultant 9,10-diformylaminoanthracene was recrystalized from formamide giving long yellow crystals mpt 439° C. Chemical analysis for C16 H12 O2 N2 was calculated N 10.60%, found N10.88%. 40 g of KOH was dissolved in 100 ml of methanol and 10 g of the 9,10 diformylaminoanthracene prepared above was added and formed a deep red brown solution. This was heated at boiling point for one hour, when red glistening crystals separated. The solution was cooled, suction filtered with the exclusion of air and the crystals washed with methanol. The crystal mass was dissolved in acetone, filtered as necessary and the filtrate carefully mixed with petroleum ether to deposit 9,10 diaminoanthracene as glistening flakes. Recrystalization from acetone gave deep red crystals. Chemical analysis for C14 H12 N2 was calculated C 80.75%, H 5.81%, N 13.44% found C 81.06%, H 5.18%, N 12.47%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[CH3:24])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.67 h
Yield: 29.5 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine was dissolved in 5 ml of dry pyridine, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 100 minutes. The same procedure as in Example 1 gave 200 mg (yield: 29.5%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Example 1 by the mixed examination.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:25](O)=[O:26])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][C:2]=1[NH:1][C:25](=[O:26])[C@H:24]([C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C@@H:28]([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)[C@H](C)Cc1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)Cc1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.07 mmol) of ethyl (−)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and 607 mg (2.28 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in a mixture of 2.0 ml of DMF and 1.0 ml of pyridine, and 1022 mg (2.69 mmol) of HATU were added at room temperature. The reaction mixture was stirred at RT overnight. The mixture was diluted with ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 998 mg (98.4% of theory) of the target compound.