Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([CH3:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:31][C:30]1[C:25]([NH:24][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=2)=[C:26]([CH3:33])[C:27]([OH:32])=[CH:28][CH:29]=1
Reactant: Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Reactant: Cc1c(O)ccc(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)Nc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
To a solution of 3-(3-fluorophenyl)-5-methyl-benzoic acid (448 mg, 1.95 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added (COCl)2 (742 mg, 5.85 mmol, 3.3 eq) and DMF (3 drops) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated in vacuo to remove the solvent and excess reagent. The solid obtained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (250 mg, 1.77 mmol, 1.0 eq) and NaHCO3 (744 mg, 8.86 mmol, 5.0 eq) in THF (15 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (396 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.[CH3:14][O:15][NH:16][CH3:17].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>CN(C=O)C>[CH3:14][O:15][N:16]([CH3:17])[C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 4-methoxyphenylacetic acid (3.3 g, 20 mmole) in dry DMF (75 mL) was added N-methoxy-N-methylamine hydrochloride (1.95 g, 20 mmole), Et3N (3.1 mL, 22 mmole), HOBt H2O (1.95 g, 22 mmole), and EDC (2.7 g, 22 mmole). The solution was stirred at RT overnight, then was concentrated in vacuum. The residue was taken up in 5% Na2CO3 solution (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (3% MeOH/CH2Cl2) to give the title compound (1.54 g, 37%) as white solid: MS (ES) m/e 210 (M+H)+.
Reaction SMILES: N1CCC(C2C=CC3OCCC4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)C=3C=2)CC1.C(OC([N:38]1[CH2:43][CH:42]=[C:41]([C:44]2[CH:45]=[CH:46][C:47]3[O:56][CH2:55][CH2:54][C:53]4[C:49](=[N:50][N:51]([C:57]5[N:58]([C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=6[Cl:68])[N:59]=[CH:60][N:61]=5)[CH:52]=4)[C:48]=3[CH:69]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[Cl:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[N:58]1[C:57]([N:51]2[N:50]=[C:49]3[C:53]([CH2:54][CH2:55][O:56][C:47]4[CH:46]=[CH:45][C:44]([CH:41]5[CH2:42][CH2:43][NH:38][CH2:39][CH2:40]5)=[CH:69][C:48]=43)=[CH:52]2)=[N:61][CH:60]=[N:59]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccccc4Cl)cc2CCO3)CC1
Agent: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Product: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(C3CCNCC3)ccc1OCC2

Procedure:
2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene from 4-{2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (490 mg, 0.9 mmol). The crude salt was partitioned between DCM and saturated aqueous sodium hydrogen carbonate, then the aqueous layer was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to reverse phase HPLC (Gemini C18 column, gradient MeOH in H2O+0.1% HCO2H) to give 154 (80 mg, 18%) as the mono formate salt. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1 H); 8.39 (s, 1 H); 8.27 (s, 1 H); 7.81-7.68 (m, 3 H); 7.64 (td, J=7.60, 1.51 Hz, 1 H); 7.09-7.03 (m, 2 H); 6.90 (d, J=8.28 Hz, 1 H); 4.19 (t, J=5.06 Hz, 2 H); 3.32 (d, J=12.42 Hz, 2 H); 3.04 (t, J=5.01 Hz, 2 H); 2.89 (dd, J=13.45, 11.09 Hz, 2 H); 2.54-2.56 (m, 1 H); 1.69 (d, J=13.20 Hz, 2 H); 1.58-1.45 (m, 2 H). LCMS: RT=7.99 min, M+H+=447
Reaction SMILES: [Mg].[CH:2]1[CH:7]=[CH:6][C:5]([N:8]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22](Cl)[CH:23]=[CH2:24]>CCOCC>[C:15]1([N:8]([CH:9]=[CH:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:24]=[CH:23][CH:22]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CCCl
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Mg]
Solvent: CCOCC
Product: C(=CN(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.0 g (40 mmol) of magnesium metal was placed in a 300 mL four-neck flask was filled with and the flask under nitrogen atmosphere. 100 mL of ether was added, and stirring was initiated. Then 30 mL of an ether solution of 8.6 g (27 mol) of 4bromotriphenylamine was slowly added by dropwise to the mixture. Adding 3 mL, refluxing was slowly started. In the course of refluxing, the addition of the diethylether solution was continued. Upon completion of the addition, refluxing was carried out for another 20 hour. The Grignard reagent solution was cooled to room temperature and was then combined with 40 mL of an ether solution of 2.1 g (27 mmol) of allyl chloride added slowly. Upon completion of the addition, the mixture was refluxed for 2 hours to complete the reaction. 50 mL of Ice-cold water was then added, and hydrolysis was carried out. The ether layer was extracted, washed once with an aqueous solution of saturated sodium bicarbonate and twice with water. The ether solution was then dried over anhydrous sodium sulfate. The ether was removed, and a white solid over 4-(N,N-diphenylamino)allylbenzene was obtained in an amount of 4.9 g (63.2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
A degassed mixture of 4-chloro-6-(4-nitrophenoxy)pyrimidine (WO 2006072589) (1.50 g, 5.96 mmol), tert-butyl carbamate (2.10 g, 17.9 mmol), cesium carbonate (2.91 g, 8.94 mmol), Pd2dba3 (0.218 g, 0.238 mmol) and Xantphos (0.276 g, 0.477 mmol) in DMF was heated at reflux for 1 hr and then maintained at RT for 16 hr. The resulting mixture was partitioned between water (100 mL) and EtOAc (100 mL) and the organic layer was separated and washed with water (2×50 mL) and brine (50 mL) and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in DCM, 0-100%, gradient elution) to afford the title compound as a beige solid (1.22 g, 85% purity, 52%); Rt 4.90 min (Method 1 basic); m/z 331 (M−H)− (ES−).
Reaction SMILES: Cl[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:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[OH:38][C:39]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31]([NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:47]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([OH:38])[CH:48]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)=[O:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Reaction time: 8.5 h
Yield: 57 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (55 mg, 0.092 mmol), methyl 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (48 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.009 mmol), and 2M Na2CO3 aq. (0.092 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The reaction mixture was added potassium carbonate (30 mg, 0.22 mmol) and iodomethane (0.050 mL, 0.80 mmol) and stirred at r.t for 8.5 hours. The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2) to afford the desired product (33 mg, 57%) as a pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.16 (dd, J=8.0 Hz and 1.1 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.31 (td, J=8.0 Hz and 1.1 Hz, 2H), 7.18-7.16 (m, 2H), 7.11-7.07 (m, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.80-6.76 (m, 1H), 6.59 (dd, J=7.7 Hz and 4.9 Hz, 1H), 6.24 (s, 1H), 5.09 (br s, 1H), 3.92 (s, 3H), 2.59-2.40 (m, 4H), 2.19-2.12 (m, 1H), 1.93-1.88 (m, 1H), 1.40 (br s, 9H). LCMS: 630 [M+H].
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[CH3:21]>C(#N)C>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:28][CH2:27]1)[CH3:36]
Reactant: CCN(CC)CCCC1CCN(CCN)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC#N
Product: CCN(CC)CCCC1CCN(CCNC(=O)N2c3ccccc3NC(=O)c3csc(C)c32)CC1
Yield: 52 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(diethylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 52% of theory. Colourless crystals, m.p. 131°-133° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][N:23](C)[CH3:24])[C:10]=2[CH:26]=1)(=[O:5])=[O:4].N#CN.C(O)(=O)C.Cl>O>[CH3:27][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:10]=2[CH:26]=1)(=[O:4])=[O:5]
Reactant: CN(C)CCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21
Agent: Cl
Agent: N#CN
Solvent: O
Solvent: CC(=O)O
Product: CNCCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21

Procedure:
3-Dimethylsulfamoyl-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 17, Step B. The cyanamide (0.28 g., 0.00071 mole) together with 2.8 ml. of glacial acetic acid, 2.0 ml. of water and 0.4 ml. of concentrated hydrochloric acid is heated to refluxing for 29 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in water. The aqueous solution is made alkaline with sodium hydroxide and the oily base that separates is extracted into ether. The washed and dried ether extract is evaporated under reduced pressure, leaving 3-dimethylsulfamoyl-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene as an oil weighing 170 mg. The base may be converted to the hydrogen oxalate salt by dissolution in absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After repeated recrystallizations from absolute ethanol and from isopropyl alcohol, the hydrogen oxalate melts at 133.5°-135.5° C., dec.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3(C#N)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]=2[NH:11]1>>[C:1]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:14]4[C:13]5[CH:30]=[CH:31][CH:32]=[CH:33][C:12]=5[NH:11][C:10]4=[O:9])[CH2:16][CH2:17]3)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCCC1
Reactant: Br[Mg]c1ccccc1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Yield: 56 %

Procedure:
This was prepared according to the procedure described in Example 1 using phenylmagnesium bromide and 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cycloheptanecarbonitrile. Yield was 56%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Pd]
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)C)cc1
Yield: 85.7 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-isopropylphenoxy)-2-methylpropionate (6.16 g), which is the product of Reference example 9(a), and palladium on carbon (5%, 1.00 g) and the reaction mixture was treated to afford the title compound (4.18 g) as a syrup.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.CN(P(N(C)C)(N(C)C)=O)C.[CH3:32][O:33][C:34]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].[C:45](=[O:47])=[O:46]>C1COCC1.O>[C:45]([CH2:44][C:42]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([O:33][CH3:32])[CH:43]=1)([OH:47])=[O:46]
Reactant: O=C=O
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(CC(=O)O)cc1OC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A dry 2 L 3-neck RBF fitted with an argon inlet, a thermometer, a magnetic stirring bar and a septum was charged with THF (220 mL) and diisopropylamine (54.6 mL, 0.39 mol, 1.2 eq). The resulting mixture was cooled to −50° C. and a solution of 2.5 M n-BuLi (156 mL, 0.39 mol, 1.2 eq) was added slowly via cannula. After 30 min of stirring at −50° C., the solution of LDA generated was cooled to −78° C. and HMPA (67.8 mL, 0.39 mol, 1.2 eq) was added, followed by a solution of methyl 2-methoxy-4-methylbenzoate 10b (57 g, 0.32 mol) in THF (220 mL), while maintaining the temperature at −78° C. The reaction mixture was stirred two more hours at −78° C., and then cannulated into a flask containing 100 g dry ice and THF (200 mL). After 30 min stirring at −78° C., the reaction mixture was allowed to warm up slowly to RT and then poured into water (1.5 L). The organic layer was separated and the aqueous layer was further extracted with ether (3×1 L). The water layer was acidified with a solution of 10% H2SO4 (150 mL) and the reaction product was extracted into CH2Cl2 (3×1.5 L). The combined organic extracts were dried over anhydrous Na2SO4, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (eluent EtOAc: hexane 3:7), followed by recrystallization from CH2Cl2:hexane 1:1 to afford pure methyl 4-carboxymethyl-2-methoxybenzoate 10c (38.8 g, 54.7% yield).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([NH2:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([NH:37][C:22]([C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)=[CH:4][CH2:5]3)=[O:23])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: NC(Cc1cccs1)c1cccs1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(Cc4cccs4)c4cccs4)[C@@]3(C)CC[C@@H]12
Yield: 49 %

Procedure:
The title compound was prepared in a yield of 49% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1,2-di(2-thienyl)ethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([NH:1][C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7])(=[O:19])[CH3:18]
Reactant: Cc1nn(C)c(C)c1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.8 %

Procedure:
Under anhydrous conditions, a mixture of 4-amino-1,3,5-trimethyl-1H-pyrazole (10 g, 80 mmol) and triethylamine (16.7 mL, 120 mmol) was treated dropwise with acetyl chloride (6.3 mL, 88 mmol). The reaction mixture was stirred at ambient temperature for 72 hours. The triethylamine hydrochloride was removed by vacuum filtration. The filtrate was concentrated in vacuo and the residue triturated with Et2O to give 9.6 g of title compound as a tan solid (72% yield, m.p. 118-119° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=O)[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.O>ClCCl.CN(C)C=O>[CH2:31]([O:30][P:26]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:9]([C@H:7]2[CH2:6][C:5]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:4]=3[C:3](=[O:19])[C@H:2]([CH3:1])[S:8]2)=[O:11])=[CH:35][CH:34]=1)([O:27][CH2:28][CH3:29])=[O:33])[CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidee hydrochloride (0.39 g) in dichloromethane (7 ml) was added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.47 g) and diethyl 4-aminobenzylphosphonate (0.41 g) in N,N-dimethylformamide (DMF) (7 ml) at 0° C., followed by the addition of 1-hydroxybenzo-triazole (HOBt) (0.28 g). This mixture was stirred at 0° C. for 1 hour and at room temperature (25° C.) for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (using MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and then recrystalized from methanolhexane to yield (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzo-thiepin-2-carboxamide (0.37 g, 44%). Colorless Prisms. Melting point 181-182° C. Optical rotation [α]D (23° C.) −187.4° (c=0.50, CHCl3).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH:59]=1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:67]3[CH2:68][CH2:69][N:64]([C:60]4[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=4)[CH2:65][CH2:66]3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: c1cncc(N2CCNCC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(c4cccnc4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), 1-pyridin-3-ylpiperazine (21 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31]C1C=C(N=C=O)C=CC=1.Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1cccc(Cl)c1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 3-chlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 223°-227° C.