Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C(S[CH:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[CH:21]2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=C(Cl)C=1.[N+]([O-])(O)=O.[Cl:30]C1C=CC=CC=1CCC(O)CN1C=CN=C1.S(Cl)(Cl)=O>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH:9]([Cl:30])[CH2:19][N:20]2[CH:21]=[CH:22][N:23]=[CH:24]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(CCC(Cn2ccnc2)Sc2c(Cl)cccc2Cl)cc1
Reactant: OC(CCc1ccccc1Cl)Cn1ccnc1
Solvent: O=S(Cl)Cl
Solvent: O=[N+]([O-])O
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
in the presence of sodium hydride reagent in dimethylformamide solvent. This substitution reaction takes a long time and gives the (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) with a poor yield (51.7%). In the next step of the butoconazole nitrate synthesis (1-[4-(chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) is treated with thionyl chloride (which is at once a reagent and a solvent) at 65-70° C. to yield 1-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole of the formula (V).
Reaction SMILES: CCOC(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.C[O:32][C:33]([C:35]1[CH:47]=[C:46]2[C:38]([N:39]3[C@H:44]([CH2:45]2)[CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41][C@H:40]3[CH3:55])=[N:37][C:36]=1[CH2:56][O:57][CH2:58][CH:59]1[CH2:61][CH2:60]1)=O.[H-].C([Al+]CC(C)C)C(C)C>>[C:51]([O:50][C:48]([N:42]1[CH2:41][C@@H:40]([CH3:55])[N:39]2[C@H:44]([CH2:45][C:46]3[C:38]2=[N:37][C:36]([CH2:56][O:57][CH2:58][CH:59]2[CH2:60][CH2:61]2)=[C:35]([CH2:33][OH:32])[CH:47]=3)[CH2:43]1)=[O:49])([CH3:52])([CH3:53])[CH3:54]
Reactant: COC(=O)c1cc2c(nc1COCC1CC1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Agent: [H-]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(COCC4CC4)nc3N21

Procedure:
This compound was prepared in analogy to example 35, intermediate c) from (4R,9aR)-6-cyclopropylmethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2,7-dicarboxylic acid 2-tert-butyl ester 7-methyl ester and diisobutylaluminium hydride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>>[C:2]1([N:1]2[C:11](=[O:12])[C:10]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]3[C:8]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
Phenylphthalimidine of the formula (II) [L. Butula, D. Kolbah and I. Butula, Croat. Chem. Acta, 44 (4), 481, (1972),], which is a starting compound of the method of this invention, may be produced according to conventional methods. For example, Compound (II) is preferably produced in a high yield by heating aniline and phthalic anhydride in the absence of a solvent to give N-phenylphthalimide in an almost quantitative yield, and then subjecting the obtained N-phenylphthalimide to reduction with zinc and acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([NH:24][C:25]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]2[CH2:12]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N=C=O
Reactant: NC(=O)c1c(-c2cccc(F)c2)nn2c1CNCC2
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N1CCn2nc(-c3cccc(F)c3)c(C(N)=O)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 1K (30 mg, 0.115 mmol) in DMF (1 mL) was added tert-butylisocyanate (28.6 mg, 0.288 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with water (2×5 mL), brine, dried over Na2SO4 and concentrated to afford the crude product as brown semi-solid. The residue was dissolved in a mixture of acetonitrile and methanol and was purified via preparative HPLC. Fractions containing the desired product (0.01 g, 24%) were combined and dried under vacuum. MS(ES): m/z=360 [M+H]+; HPLC Ret. Time 6.66 min. and 6.14 min. (HPLC Methods A and B); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (m, 2H), 7.25 (m, 2H), 7.25 (bs, 1H), 6.98 (bs, 1H), 6.26 (s, 1H), 4.69 (s, 2H), 4.11 (t, J=5.7 Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 1.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][C:23](=O)[O:24]C2C=CC=CC=2)[N:16]=1.Cl>O1CCOCC1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][C:23]([NH:12][S:9]([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][O:2][CH3:1])(=[O:11])=[O:10])=[O:24])[N:16]=1
Reactant: COCc1ccsc1S(N)(=O)=O
Reactant: COc1cc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1ccsc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.52 g of phenyl N-(4-methoxy-6-methylpyrimidin-2-yl)carbamate in 25 mL of 1,4-dioxane is added 0.3 mL of 1,8-diazabicyclo[5.4]undec-7-ene. After being stirred for two hours at ambient temperature and pressure, the reaction mixture is poured onto 25-50 g of ice and the resultant mixture is acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product in sufficiently pure form for the purposes of this invention.
Reaction SMILES: [F:1][C:2]([C:8]([CH3:10])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4].[Br:11]Br>S(=O)(=O)(O)O>[Br:11][CH2:10][C:8](=[O:9])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: CC(=O)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: O=C(CBr)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl pentafluoroethyl ketone (3.9 g, 0.02407 mole) (JACS, 78, 2268-70 [1956]) was stirred in concentrated sulphuric acid (10 ml) at room temperature under a dry-ice condenser. Bromine (1.92 g; 0.012035 mole) was added slowly over two hours with vigorous stirring. The mixture was then stirred for one hour at room temperature and then at 50° C. for one hour. The resulting amber solution was distilled at atmospheric pressure, yielding one main fraction of 4.41 g (76%), boiling at 94-97° C. The mass spectrum confirmed the structure, showing parent ions at 240 and 242 m/e corresponding to C4H2BrF5O (2 isotopes of Br).
Reaction SMILES: N1C=CC=CC=1.[N:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[NH2:13][C:12]1[N:7]=[C:8]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(N)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(N)n1
Temperature: 0 °C
Yield: 50 %

Procedure:
Pyridine (0.130 mL, 1.60 mmol) was added to pyridine-2,6-diamine (350 mg, 3.21 mmol) in DCM (6.4 mL). The reaction mixture was cooled to 0° C., and then methanesulfonyl chloride (0.124 mL, 1.60 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-100% acetone/hexanes, linear gradient) to afford N-(6-aminopyridin-2-yl)methanesulfonamide (˜50% purity) that was used without further purification. MS ESI calc'd. for C6H10N3O2S [M+H]+ 188. found 188.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH2:83][CH3:84])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCN(CC)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0173 g (0.135 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0368 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-ethyl-piperidin-4-yl)-benzamide (I-196) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(OCC2CC2)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and (bromomethyl)cyclopropane (14 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 12 mg (41%) of 3-(2-pyridyl)-5-(3-cyano-5-cylopropylmethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 3.95 (d, 2H), 1.21 (m, 1H), 0.72 (m, 2H), 0.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:4]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 3,3-dimethyl-1-indanone (20,0 q, 0,125 mol) prepared by the method described by R. Knorr et al., Leibig's Annalen, 1207 (1980) and phenylhydrazine (12.3 cm3, 0.125 mol) in glacial acetic acid (200 cm3), was heated to reflux. Concentrated hydrochloric acid (10 cm3) was added via the condenser, and boiling continued for a further 2 hours. The solution was allowed to cool, and then poured into water (500 cm3). The water was extracted with diethylether three times, the combined extracts were washed with brine and water, and dried (MgSO4). The solvent was removed, and petrol (60°-80° C.) added to the residue. The suspension was heated until boiling, The solid product was filtered off and the mother liquor concentrated. On cooling, more solid was obtained, and additional product separated out as the mother liquor was concentrated further. The solids were combined and crystallised from petrol to give the title compound. Yield: 10,2 g (35%). M.p. 160 ° C. 1H NMR: (CDCl3) δ: 1.60 (6H, s,), 7.1-7.7 (8H, m,), 8.16 (1H, s,).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([NH:36][CH2:37]C(C)C)[CH3:35])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:44][CH:45](C)[CH2:46]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:41]([NH2:43])=[O:42])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([N:36]5[CH2:37][CH2:46][CH2:45][CH2:44]5)[CH3:35])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C(C)NCC(C)C)c4)cc23)CC1
Reactant: CC(C)CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C(C)N5CCCC5)c4)cc23)CC1
Yield: 71 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (101 mg, 1.98 mmol) for (2-methylpropyl)amine to afford 29.2 mg of the title compound (71%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:32])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][C:16]=2[CH2:28][NH:29][CH2:30][CH3:31])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH2:2]([O:4][C:5](=[O:32])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][C:16]=2[CH2:28][N:29]([C:36]([CH:33]2[CH2:35][CH2:34]2)=[O:37])[CH2:30][CH3:31])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(-c2ccc(F)cn2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(F)cn3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-4′-(5-fluoro-pyridin-2-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1(C)C(C)=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc(Cl)c1OC(=O)c1ccc(CCl)cc1

Procedure:
88.5 g (0.5 mole) of 2,4-dichloro-6-methylphenol, 180 ml of dry xylene, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride and 0.5 ml of pyridine were refluxed for 24 hours in a weak current of nitrogen with the exclusion of moisture. After cooling, the slightly turbid (pyridine hydrochloride), orange-colored solution was filtered free of a small amount of a blackish brown resin, and the filtrate was freed of xylene at diminished pressure. The residue (165 g=100%) crystallized after two days of standing to a light brown crystal mass, which was triturated in 200 ml of ice-cold petroleum ether and suction filtered. After drying, nearly colorless crystals were obtained with a melting point of 71°-73° C. Recrystallization from petroleum ether (1:10) yielded white needles melting at 74°-75° C.; no change in the melting point was brought about by repeated recrystallization.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:24][O:23][C:22]1[C:2]([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: COc1ccc(B(O)O)cc1
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2cc3c(cc2OC)N(C)C(=O)CN=C3c2cccc(C#N)c2)cc1
Yield: 53 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used p-methoxyphenyl boronic acid. The title compound (85 mg) was obtained as a white solid, (yield=53%).
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:8][C@H:7]([NH:9]C(=O)OC(C)(C)C)[CH2:6]1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][C@H:7]1[CH2:8][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(C)(C)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)[C@H]1C[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [trans-3-(2-hydroxypropan-2-yl)cyclobutyl]carbamate (250 mg, 1.09 mmol) and TFA (10 mL) in DCM (10 mL) was stirred at RT for 2 hours. The resulting mixture was then concentrated in vacuo to afford 2-(trans-3-aminocyclobutyl)propan-2-ol which was used in the next step directly.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]3)=[CH:8]2)=[CH:2]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1ccoc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.7 g (11.9 mmol) of 1-furan-3-ylmethyl-5-methoxy-3-piperidin-4-yl-1H-indole and 3 g (13.9 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up, 3.2 g (57% of yield) of the expected acid were obtained.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH3:14][C:15]1[CH:16]=C(O)C=[CH:19][CH:20]=1.Cl>ClCCl>[C:5]([O:4][C:1]1[CH:14]=[C:15]([CH3:16])[CH:20]=[CH:19][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Acetic anhydride (519 mg) and pyridine (439 mg) were added to a solution of 3-methylphenol (500 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/8) to give the title compound (583 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[CH:21])[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC>CN(C=O)C.[Cu]I>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[C:21][C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:25]4[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(CC#Cc4ccccc4-c4ccccc4)CC3=O)ccc12
Temperature: 80 °C
Yield: 5.3 %

Procedure:
A solution containing 1-(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (50 mg, 0.17 mmol), EXAMPLE 283, 2-bromobiphenyl (44 mg, 0.19 mmol), Et3N (69 mg, 0.68 mmol), (Ph3P)4PdCl2 (6 mg, 0.008 mmol), and CuI (1 mg, 0.005 mmol) in anhydrous DMF (2 mL) is warmed at 80° C. for 1 hours. The reaction mixture is cooled to 50° C. and the solvent is removed over 16 h under a stream of nitrogen. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2) to afford a colorless gum which is triturated with ethyl alcohol to provide 4 mg (5%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.03 (s, 2H), 3.14 (m, 2H), 3.31 (m, 2H), 3.50 (s, 2H), 7.21-7.55 (m, 11H), 7.76 (br s, 2H), 8.18 (d, J=8.6 Hz, 1H), 8.36 (s, 1H) ppm; MS (ion spray): m/z 448 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of Example 1 (0.20 g, 0.66 mmol) in DMF (5 mL) was added 2-picolyl chloride hydrochloride (0.10 g, 0.61 mmol) and triethylamine (0.24 mL, 1.72 mmol). The subsequent mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted into ethyl acetate (25 mL) and washed with water (25 mL) followed by brine (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.07 g, 36%); 1H NMR (400 MHz, CDCl3); δ 1.73-1.80 (m, 3H), 2.05 (m, 1H), 2.40 (m, 1H), 3.02-3.08 (m, 2H), 3.71 (d, J=13.6 Hz, 1H), 3.83 (m, 1H), 3.91 (s, 2H), 3.95 (m, 1H), 4.25 (d, J=13.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 4H), 7.25-7.27 (m, 2H), 7.41 (m, 1H), 7.61 (m, 1H), 8.53 (m, 1H); MS (m/z) 359.2 (M+1); LC (100.0%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C(OCC)(=O)C>[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: NCc1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: S=C=NCc1ccccc1

Procedure:
Benzylamine (1.5 g) and triethyl amine (2.9 g) were dissolved in anhydrous ethyl acetate (50 ml) and stirred under ice cooling. Thiophosgene (4.9 g) dissolved in ethyl acetate (50 ml) was slowly added to the stirred solution. The solution was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded (isothiocyanatomethyl)-benzene which was used in the next step without purification. 1H NMR, CDCl3, 4.72 (2H, s), 7.30-7.40 (5H, m).