Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=2)[CH:26]=[CH:25]1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:33]([C:30]2[CH:31]=[C:32]3[C:27]([CH:26]=[CH:25][NH:24]3)=[CH:28][CH:29]=2)=[O:34])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2cc[nH]c2c1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with indole-6-carboxylic acid, using general method D, to give 1H-indole-6-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Off-white solid. MS 481.5 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Br)nc1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of methyl 3-amino-6-bromopicolinate (2.31 g, 10 mmoles) in 2:1 THF/MeOH (51 mL) was added 1.0 M LiOH (17 mL, 17 mmoles). After stirring for 16 hours, 1 N HCl (17 mL, 17 mmoles) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with cold H2O (4×20 mL) and pumped on yielding 3-amino-6-bromopicolinic acid (97%). LCMS (m/z): 216.9 (MH+); LC Rt=1.93 min.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4](=O)[CH2:5][C:6]([O:8]CC)=[O:7].[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+]>C(O)C>[CH2:23]([NH:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([N:13]2[C:4]([CH:3]=[C:2]([CH3:1])[CH3:12])=[C:5]([C:6]([OH:8])=[O:7])[N:15]=[N:14]2)=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)C=C(C)C
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C=C(C)C)cc1
Temperature: 50 °C
Reaction time: 10.5 h
Yield: 78.2 %

Procedure:
Ethyl 5-methyl-3-oxo-4-hexenoate (1.10 g, 6.56 mmol, 1.1 eq.) obtained in Example 95a) and 4-azido-N-ethylbenzamide (purity 90%, 1.23 g, 5.82 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (550 mg, 7.82 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 50° C. for 10.5 hr. Ethanol was evaporated from the reaction mixture, and the residue was diluted with 2% aqueous sodium carbonate solution (40 ml) and washed with ethyl acetate (40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (2:1, 50 ml), acidified (pH<3) with 6N hydrochloric acid and extracted three times with ethyl acetate (50 ml) and ethyl acetate-THF (3:1, 40 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a grayish white powder (1.43 g, 4.55 mmol, 78.2%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:40]1[CH2:42][CH2:41]1)(=O)=O.[CH3:45][O:46][C:47]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)=[O:48].COC(C1C=CC(B(O)O)=CC=1)=O>>[CH:40]1([N:11]2[C:12]3[C:8](=[C:7]([C:51]4[CH:50]=[C:49]([CH:54]=[CH:53][CH:52]=4)[C:47]([O:46][CH3:45])=[O:48])[CH:15]=[C:14]([C:16]([N:18]4[CH2:23][CH2:22][C:21]5([CH2:32][C:31](=[O:33])[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([C:34]7[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=7)[CH:29]=6)[O:24]5)[CH2:20][CH2:19]4)=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:41][CH2:42]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Agent: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(-c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc3c2ccn3C2CC2)c1

Procedure:
The intended compound was produced according to the procedure described in Example 28-1 but using 1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl trifluoromethanesulfonate and [3-(methoxycarbonyl)phenyl]boronic acid in place of 8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl trifluoromethanesulfonate and [4-(methoxycarbonyl)phenyl]boronic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][C:19]([CH3:22])=[CH:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)=[O:12])[C:3]1=[O:15]
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cnc(NC(=O)c2c(O)cc(C)n(C)c2=O)s1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 73.2 %

Procedure:
212 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 105 mg of 2-amino-5-methylthiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 188 mg of 1,6-dimethyl-4-hydroxy-N-(5-methylthiazol-2-yl)-2-oxo-1,2-d ihydropyridine-3-carboxamide (hereinafter, referred to as present compound 20) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)acetic acid (25.0 g, 122 mmol) was dissolved in MeOH (122 mL) at ambient temperature. Sulfuryl dichloride (8.89 mL, 122 mmol) was then added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a light yellow oil which was used without further purification. MS (m/z)=219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH2:23][NH2:24]>C(#N)C>[NH2:11][C:10]1[NH:24][N:23]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: N#CC(C(=O)c1ccc(Cl)cc1)c1ccncc1
Reactant: NN
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: Nc1[nH]nc(-c2ccc(Cl)cc2)c1-c1ccncc1
Yield: 54.3 %

Procedure:
A solution of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (3.50 g, 13.6 mmol) in 40 mL acetonitrile and phosphorous trichloride (14.2 ml, 163 mmol) was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in toluene and concentrated again. The residue was then taken up in ethanol (150 mL) and treated with anhydrous hydrazine (1.71 mL, 54.4 mmol). The reaction mixture was heated to reflux for 3 hours, cooled, and concentrated in vacuo. The residue was triturated with a mixture of ethanol and dichloromethane (1:4), and filtered. The solid was washed with the ethanol/dichloromethane mixture, and dried to give 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (2.0 g, 54%): m.p. >300° C. 1H NMR (DMSO/300 MHz) δ 8.40 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.11 (d, 2H), 5.05 (s, 2H). ESLRMS m/z 271 (M+H). ESHRMS m/z 271.0752 (M+H, C14H11N4Cl requires 271.0750).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[NH2:10][C:11]1[C:12]([C:18](O)=[O:19])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1>CN(C=O)C.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[C:18](=[O:19])[N:9]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:10][C:11]=2[CH:16]=1
Reactant: COC1=NCCCCC1
Reactant: Nc1cc(Br)cnc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ncc(Br)cc2nc2n1CCCCC2

Procedure:
A solution of 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (1.0 g, 8.8 mmol) and 3-amino-5-bromopicolinic acid (1.9 g, 8.8 mmol) in DMF (70 mL) was stirred at 130° C. for 48 h. The reaction mixture was diluted with H2O (300 mL) and extracted with DCM (3×300 mL). The combined organic layers were washed with saturated sodium carbonate and brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI):294, 296 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9](I)[CH:10]=1)=[O:5])[CH3:2].CCN(CC)CC.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)#[CH:22]>C(#N)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH3:13])[CH:8]=[C:9]([C:22]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cccc(OC)c1
Reactant: CCOC(=O)c1cc(I)cn1CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Argon was gently bubbled to a mixture of ethyl-4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester (4.1 g, 14 mmol), CuI (0.14 g, 0.76 mmol), Et3N (40 ml, 287 mmol) and tetrakis(triphenylphosphosphine)palladium (0) (0.64 g, 0.554 mmol) in ACN (20 mL) over 5 minutes. A prepared solution of 1-ethynyl-3-methoxy-benzene (2.03 g, 15.4 mmol) in ACN (5 mL) was added into it and the new mixture was reflux under Nitrogen for 3 hours. The resulting brown colored reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with water and extracted with ether. The combined ether extracts were washed with saturated aqueous solution of NH4Cl, brine, dried (MgSO4) and filtered. Evaporation and purification by flash chromatography on silica gel (Hexane/EtOAc 9.7/0.3) gave the title compound as a yellow brownish oil (3.6 g, 84% yield), 1H NMR (400 MHZ, CDCl3) δ 1.31-1.34 (t, 3H), 1.38-1.40 (t, 3H), 3.78 (s, 3H), 4.25-4.27 (q, 2H), 4.30-4.33 (q, 2H), 6.83 (m, 1H), 6.89 (m, 1H), 7.06 (m, 3H), 7.19 (m, 1H), MS m/e (M+H)+ 298.1.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C.[Cu-]=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([O:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Oc4ccccc4)c3c2CC1

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.85 g, 5.00 mmol), phenol (0.94 g, 10.0 mmol), copper (I) oxide (0.036 g, 0.25 mmol), and cesium carbonate (4.89 g, 15.0 mmol) in o-xylene was reacted in a similar manner to Preparation 10 to afford 0.55 g (29%) of colorless solid as the title compound: mp 179-182° C. (CH2Cl2/hexane); IR (KBr) 1601, 3226 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.40-8.24, 7.43-7.34, 7.05-6.90, 6.55-6.50, 4.00-3.90, 3.64-3.55, 3.29-2.84; 13C NMR (75.5 MHz, CDCl3) δ 171.8, 158.1, 150.1, 137.0, 136.9, 135.0, 129.7, 129.3, 128.6, 126.5, 122.6, 122.0, 118.1, 117.6, 110.1, 109.4, 106.5, 51.2, 45.2, 28.9, 27.2; MS (EI) m/z 382 (M+); HRMS cacld for C25H22N2O2+H: 383.1759, found: 383.1749; Anal. Calcd. for C25H22N2O2.1/2H2O: C, 76.70; H, 5.92; N, 7.17. Found: C, 76.72; H, 5.79; N, 7.15.
Reaction SMILES: [H-].[Na+].C([O:6][CH2:7][CH:8]([F:10])[F:9])(=O)C.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[F:9][CH:8]([F:10])[C:7](=[O:6])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)OCC(F)F
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 46.7 g (1.168 mol) of sodium hydride (60% dispersion in paraffin) were added to 600 ml of tetrahydrofuran. A mixture of 125 g (1.008 mol) of difluoroethyl acetate and 88.7 g (1.010 mol) of ethyl acetate was added dropwise at 35° C., while the temperature was kept below 40° C. The mixture was then further stirred at room temperature overnight. The reaction mixture was carefully poured into 1.7 l of ice water and the pH adjusted to pH 3 by addition of sulphuric acid. The mixture was extracted twice, each time with 500 ml of methyl tert-butyl ether, and the combined organic phases were washed twice with saturated sodium chloride solution, dried over sodium sulphate, concentrated at 40° C. and 150 mbar and distilled at 60 mbar (Vigreux column). The product was obtained at 85-87° C. as a colourless liquid (104 g, 62% of theory with a purity of >99% (GC)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (0.6 gram) and 2-chlorobenzoyl isocyanate (0.7 gram) were reacted according to the teaching of Example 7. The identity of the product was confirmed by NMR, yield 920 mg, m.p. 228°-231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([OH:15])(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])(=[O:14])[CH3:13]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)O
Product: CC(=O)OCC(=O)c1ccc(C)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-methylphenacyl bromide reacted with 5 grams of acetic acid to obtain 4-methylphenacyl acetate, m.p. 85°-85° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:38][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:22]1[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Reactant: Oc1cccc(F)c1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3cccc(F)c3)cc12

Procedure:
6-[3-(3-Fluoro-phenoxy)-propoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 46% overall yield using the method described in example 161, starting from 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 101A) and 3-fluorophenol.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26].Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[Si:25]([CH3:28])([CH3:27])[CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1Cc2ccc([Si](C)(C)C)c(S(=O)(=O)NC(C)(C)C)c2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of N-t-butyl-2,3-dihydro-2-methylbenzo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 20 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 3.0 ml of chlorotrimethylsilane. The mixture was stirred at room temperature for 2 hours and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to a crude solid which was suspended in chlorobutane/hexane and filtered to give 2.0 g of the title compound as a beige solid, m.p. 119°-124° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:36][C@H:37]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]>CN(C=O)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:36][C@H:37]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
44 g BocGlyOH (0.25 moles) is dissolved in 250 ml DMF, together with 29 g HOSu. After cooling to -20° C. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 95 g ValOBzl, pTos is added together with 35 ml TEA. After stirring overnight at room temperature, DCU is filtered off, DMF removed and the resulting oil taken up in EtAc and washed with sat. NaCl, sat. NaHCO, and 10% citric acid. The EtAc is dried with Na2SO4, removed by vacuum evaporation and the resulting crystalline mass dried in a desiccator. Yield: 59 g (65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]Br.[CH3:11][NH2:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][CH2:11][NH2:12]
Reactant: CN
Reactant: Cc1cccc(CCBr)c1
Product: Cc1cccc(CCCN)c1
Temperature: 80 °C

Procedure:
A mixture of 3-methylphenethyl bromide (2.22 g) and 33% ethanolic methylamine solution (30 ml) was heated in a bomb at 80° C. for 16 hours and evaporated. The residue was partitioned between water and dichloromethane and the organic layer dried over MgSO4 and evaporated. The residue was purified by 421 chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil, 0.44 g (27%), which was used directly in the preparation of Example 21 without characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 76.2) and (3S,4S)-pyrrolidine-3,4-diol. The crude product was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 10% to 100% EtOAc) to give the title product as a white solid. UPLC-MS (Condition 8) tR=1.02 min, m/z=477.1/478.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:38].[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2([NH2:30])[CH2:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 90.6 %

Procedure:
tert-Butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (36.4 mg, 0.0708 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 15.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (33.6 mg, 90.6%) as yellow solid. 1H NMR (DMSO-d6) 400 MHz δ: 8.72 (br s, 2H), 8.68 (s, 1H), 8.16 (dd, J=4.8, 1.8 Hz, 1H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.61-7.55 (m, 2H), 7.42-7.27 (m, 4H), 7.13-7.07 (m, 1H), 6.98 (dd, J=7.8, 1.8 Hz, 1H), 6.81 (dd, J=7.8, 4.8 Hz, 1H), 4.27 (br s, 3H), 2.64-2.43 (m, 4H), 2.26-2.12 (m, 1H), 1.89-1.74 (m, 1H); LCMS: 414 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-:10].[Na+]>O.[Ni].[Pd]>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([C:7]([OH:10])=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: [OH-]
Agent: [Ni]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(C(=O)O)O1
Reaction time: 2 h
Yield: 86 %

Procedure:
40.7 g (308 mmoles) of a glycerin ketal mixture containing 97.5% by weight of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 12.2 g (305 mmoles) of sodium hydroxide were dissolved in 366 ml of water. After transferring the mixture to a nickel shaker-type autoclave, the solution was heated to about 80° C. under a pressure of 25 bar in the presence of 4 g of an activated carbon containing 5% by weight of palladium with agitation for about 2 hours. The pressure in the autoclave rose briefly to 30 bar, subsequently fell back to 25 bar and, after another hour, increased to 63 bar. After 2 hours, the pressure remained constant at 53 bar. The autoclave was then vented. The pH of the solution was adjusted, the water in the solution was distilled off, and the remaining residue was hot extracted in the same manner as described in Example 2. The 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, Na salt was isolated in a yield of 86% of the theoretical. The melting point of the salt was 243°-246° C.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc(-c3ccc(C)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-p-Tolyl-thiazol-2-ylamine (38.1 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (13.5 mg, 0.0438, 21.9%). ESI-MS m/z calc. 308.1, found 309.0 (M+1)+ Retention time 3.72 minutes.