Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:16](=[CH2:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: [Li]CCCC
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CCCCCCC(=O)OCC)c1ccc2ccccc2c1
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (469 mg,1.31 mmol) in THF (6 mL) pre-cooled to 0° C. under nitrogen atmosphere was added dropwise n-butyllithium (1.42M solution in hexanes, 905 μL, 1.28 mmol) and stirred over 20 minutes. To this a THF (4mL) solution of 49g (82 mg, 0.262 mmol) was transferred via cannula. The yellow mixture was stirred over 30 minutes and quenched with a saturated aqueous solution of ammonium chloride, as the yellow color immediately disappeared. The solvent was removed by evaporation in vacuo and the aqueous residue was partitioned between water and ethyl acetate. The aqueous layer was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography (5% to 8% diethyl ether in hexane) to afford the title compound 168 (43 mg) in 52% yield. 1H NMR: (CDCl3) δ: 7.85-7.78 (m, 4H), 7.58 (dd, J=8.8, 1.9 Hz, 1H), 7.48-7.44 (m, 2H), 5.42 (d, J=1.1 Hz, 1H), 5.16 (d, J=1.4 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.28 (d, J=7.4 Hz, 2H), 1.64-1.49 (m, 4H), 1.39-1.33 (m, 4H), 1.25 (t, J=7.1 Hz, 3H). MS (ESI)=311 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: C[O-]
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3cccc(C(F)(F)F)c3)c(Cl)nc12
Agent: CO[Na]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.87 g, 1.83 mmol, Intermediate 15: step c) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene was heated in a sealed tube at 110° C. for 12 hours. Starting material was still present, therefore additional NaOCH3 (198 mg, 3.66 mmol) was added and stirring was continued at 110° C. for another 24 hours. The mixture was then cooled to room temperature, diluted with DCM, stirred at room temperature for 30 minutes, and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the white solid product was precipitated from MeOH, filtered and dried to provide the title compound.
Reaction SMILES: C([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)(C)(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([CH:14]([O:13][C:8]1[CH:7]=[N:6][NH:5][C:10](=[O:11])[C:9]=1[Cl:12])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH:23]([O:25][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH3:24])=[CH:19][CH:20]=1)([CH3:20])([CH3:16])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of the product of Example 7B (200 mg, 0.548 mmol) in pyridine (10 mL) was added p-toluenesulfonyl chloride (209 mg, 1.096 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Monitoring by LC-MS showed a 1:1 mixture of starting material and product. The reaction was diluted with ethyl acetate and washed with 5% CuSO4 until a light blue aqueous solution was maintained. The organic layer was then dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (3:1 hexane:ethyl acetate to 100% ethyl acetate) to recover the starting material (90 mg) and the product as a clear oil (74 mg, 47% yield based on recovered starting material). 1H NMR (600 MHz, CDCl3): 7.80 (d, 2H, J=8.3 Hz), 7.72 (s, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.1 Hz), 7.13 (d, 2H, J=8.1 Hz), 5.27 (s, 2H), 4.66 (m, 1H), 2.65 (m, 1H), 2.54 (m, 1H), 2.45 (s, 3H), 1.94 (m, 1H), 1.81 (m, 1H), 1.63 (s, 9H), 1.26 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[CH:3]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1>>[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31]([C:2]5[CH:11]=[N:10][C:5]6=[N:6][CH:7]=[CH:8][N:9]=[C:4]6[CH:3]=5)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1
Reactant: Brc1cnc2nccnc2c1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6nccnc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 7-bromopyrido[2,3-b]pyrazine and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 9.56 (s, 1H), 9.13 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.14 (d, 1H), 4.71 (s, 2H), 4.41 (m, 2H), 3.85 (m, 2H), 2.71 (t, 2H), 2.49 (s, 2H), 1.62 (t, 2H), 0.84 (s, 6H); MS (EI) for C26H26N6O: 439 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:13]=1)=[C:8]([CH2:11]O)[O:9][CH:10]=2.O=S(Cl)Cl.[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([CH2:11][N:27]3[CH2:28][CH2:29][C:24]([CH2:23][C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:32][CH:31]=4)([OH:30])[CH2:25][CH2:26]3)[O:9][C:10]=2[CH:13]=1
Reactant: COc1ccc2coc(CO)c2c1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COc1ccc2cc(CN3CCC(O)(Cc4ccc(C)cc4)CC3)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
To a solution of 6-methoxy-2-benzofuranmethanol (89 mg, 0.5 mmol) in dioxan (3 ml) at room temperature was added dropwise SOCl2 (0.11 ml, 1.5 mmol). After 1.5 hr, the reaction mixture was concentrated at room temperature under high vacuum. The residue was dissolved in dioxan (3 ml) and treated with 4-(4-methyl-benzyl)-piperidin-4-ol (225 mg, 1.1 mmol). After stirring 17 hr at room temperature, the solvent was evaporated. The residue was taken up in H2O (4 ml) and extracted with CH2Cl2 (6×4 ml). The combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (19:1) to provide 1-(6-methoxy-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (140 mg, 77%) as a yellow oil, MS:m/e=366.3 (M+H−+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][C:14](=[O:21])[CH2:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([O:25][C:26](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:22][O:25][CH:26]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)[C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: O=C1Cc2cc(OCCN3CCOCC3)ccc2C(=O)N1
Reactant: CC(=O)OC(C)=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(OCCN3CCOCC3)cc21

Procedure:
A mixture of 6-(2-morpholin-4-yl-ethoxy)-4H-isoquinoline-1,3-dione (390 mg, 1.34 mmole), 10 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.1 mL, 10.1 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the residue treated with 2:1 hexanes/ethyl acetate, the product is collected by filtration, a yellow solid, 230 mg, (52%), MS (ES+): m/z 333.2 (M+H), used as is in the next step.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([F:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:14][NH2:15])=[O:2])=[CH:5][C:6]=1[F:11]
Reactant: NN
Reactant: COC(=O)c1ccc(Br)c(F)c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(Br)c(F)c1
Temperature: 70 °C

Procedure:
A mixture of compound 4-bromo-3-fluoro-benzoic acid methyl ester (1 g, 4.29 mmol), hydrazine hydrate (2.2 mL, 42.9 mmol) and MeOH (20 mL) was heated at 70° C. for overnight. Concentrated, diluted with EtOAc (300 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated give the desired product 2AR (0.9 g, 90%).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.[CH3:21][C:22](=NO)[C:23](=O)CC.C1C2C(=CC=CC=2)C=CC=1C=O>>[CH2:8]([C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[CH:21][CH:22]=[CH:23][CH:20]=3)[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:13]
Reactant: CCC(=O)C(C)=NO
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: O=Cc1ccc2ccccc2c1
Product: CCc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde gave 5-ethyl-4-iodomethyl-2-naphthalen-2-yloxazole.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][CH2:7][CH:8]([CH2:42][OH:43])[CH2:9][CH2:10][N:11]1[C:19](NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:17]2[C:12]1=[N:13][C:14](OC)=[N:15][CH:16]=2.C(=O)(O)[O-].[Na+].[N:49]1C=CC=CC=1>O>[NH2:49][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][OH:6])[CH2:42][OH:43])=[CH:16][N:15]=1
Reactant: c1ccncc1
Reactant: COc1ncc2nc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n(CCC(CO)CO)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of phosphorus oxychloride (93 μl, 1.0 mmol) in pyridine (2 ml) was added dropwise over 45 minutes a solution of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)-2-monomethoxytritylaminopurine (0.46 g, 0.9 mmol) in pyridine (4 ml). The solution was stirred for a further 20 minutes at room temperature and was then added dropwise to a solution of sodium bicarbonate (0.34 g, 4.0 mmol) in water (6 ml). The solvent was removed and the residue was taken up in 80% acetic acid (9 mm) and the solution was stirred at 70° for 25 minutes. The solvent was removed and the residue was taken up in water and brought to PH 6 by addition of ammonia. The solution was extracted twice with chloroform and the solvent was removed. The residue was purified by preparative high pressure liquid chromatography on a C18 reverse-phase μ-Bondapack column eluting with 4% methanol in ammonium acetate buffer (pH 4.5, 50 mM) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl) purine 4':4"-phosphate as a white powder (225 mg, 75%); λmax (H2O) 220, 242, and 303 nm; νmax (KBr) 2900-3200 (br), 1705, 1615, and 1580cm-1 ; &H [(CD3)SO] 1.63 (1H, m, 3'-H), 1.74 (2H, q, J 7.OHz, 2'-H), 3.80 (2H, q, J 9.2Hz, 2×Hax), 3.98 (2H, ddd, J 14.3, 10.9, and 3.5Hz, 2×Heq), 4.08 (2H, t, J 7.1 Hz, 1'-H), 6.51 (2H, s, D2O exchangeable, 2-NH2), 8.10 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 36.41; H, 5.18; N, 22.38%. C10H14N5O4P . 0.3 NH3. 1.5H2O requires C, 36.25; H, 5.45; N, 22.40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[C:12]([NH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:20]1[C:19]2[C:23](=[CH:24][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=2)[NH:22][C:21]1=[O:25]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: COc1ccc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde was condensed with 6-acetamido-2-oxindole to give N-[3-(3-bromo-4-methoxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:80][CH2:81][N:82]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:83][CH2:84]1)([CH3:73])([CH3:71])[CH3:72]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-Bis-(4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred suspension of 0.489 g (0.94 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml of DMF and followed by N,N-diisopropylethylamine 0.242 g (1.88 mmol) while the temperature was maintained below 5° C. during the addition. The mixture was stirred for 10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 6 N HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with 10% solution of potassium hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated brine solution, and dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. Percentage purity: 36.3%, (M+1)=567.2. 1H NMR (DMSO-d6): δ 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (1H, t), 6.95 (1H, d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>N1C=CC=CC=1>[S:7]([O:18][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: C=CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In this preparation 1.0 mole of p-toluenesulfonyl chloride is dissolved in 700 ml. of pyridine at 0° C, under nitrogen, and then 1.0 mole of hex-5-en-1-ol is added dropwise. The mixture is then stirred at room temperature for 16 hours, then poured into ice water and extracted with ethyl ether. The ethyl ether extract is then sequentially washed with water, 10% aqueous hydrochloric acid, water, aqueous 10% sodium bicarbonate solution and water, and then dried over magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording hex-5-en-1-ol tosylate as a residue.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[CH3:28][C:29]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:30]=1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[F:38][C:35]1[CH:36]=[CH:37][C:29]([CH3:28])=[C:30]([CH:34]=1)[C:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:32]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1C(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 22.7 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.35 g) in dry pyridine (10 ml) and 2-methyl-5-fluorobenzoyl chloride (0.22 g), the title compound (0.11 g) was obtained as an amorphous pale yellow solid, MS, m/z: 490 (M)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([O-:22])=[O:21].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[OH:27][CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
N,N-Diethyl-4-iodobenzamide (5.0 g, 16 mmol) was dissolved in THF (150 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (15 mL, 1.07 M solution in hexane, 16 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was then canulated into 3-nitrobenzaldehyde (2.4 g, 16 mmol) in toluene/THF (approx. 1:1, 100 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 2 (2.6 g, 50%). 1H NMR (CDCl3) δ 1.0-1.3 (m, 6H), 3.2, 3.5 (2m, 4H), 5.90 (s, 1H), 7.30-7.40 (m, 4H), 7.50 (m, 1H), 7.70 (d, J=8 Hz, 1H), 8.12 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCOC(=O)CCCN
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100 ml) was treated with ethyl 4-aminobutanoate (720 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](Cl)=[O:6].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:2]([F:1])[CH:3]=1)([CH3:32])[CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)#[N:18]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=494, RT=0.73 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>C(O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 30.6 %

Procedure:
In 100 ml of ethanol were dissolved 18 g of 1-bromo-n-decane and 9 g of 3-chloro-4-hydroxybenzoic acid, an aqueous solution of 40 g of sodium hydroxide in 100 ml of water was added to the above solution, and the mixture was heated and refluxed for 10 hours. Then the reacted solution was made weakly acidic by an addition of 1N hydrochloric acid and thrown in an enough quantity of water to precipitate the reaction product. The precipitate was recovered by filtration and recrystallized from ethanol to obtain 5 g of 3-chloro-4-decyloxybenzoic acid, then 15 g of thionyl chloride was added to 3 g of 3-chloro-4-decyloxybenzoic acid, and a reaction was carried out under reflux for 3 hours. The unreacted thionyl chloride was removed by distillation under a reduced pressure to obtain 3-chloro-4-decyloxybenzoic acid chloride quantitatively. Then the product was dissolved in a diethyl ether/THF (1/1) mixed solvent, 2.3 g of 4,4'-acetoxybiphenol and 2 g of triethylamine were added to the solution successively, and a reaction was carried out at room temperature with stirring overnight. The reacted solution was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water, in this order, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, the reaction product was recovered by the silica gel chromatography, then the reaction product was dissolved in 100 ml of a THF/methanol (9/1) mixed solvent, a 1N aqueous solution of lithium hydroxide was added to the resulting solution which was cooled with ice-cold water, and a reaction was carried out with stirring for 30 minutes. Then the reacted solution was made weakly acidic by addition of 1N hydrochloric acid, extracted with a diethyl ether/benzene (1/1) mixed solvent, and the extract was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water in this order. The organic phase was recovered and dried with anhydrous magnesium sulfate, and the organic solvent was evaporated to obtain a product. The product was recrystallized from an n-hexane/ethanol mixed solvent. The compound in which Z is fluorine can be similarly obtained by using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.