Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([CH2:12][C:13]([O:15]CC)=O)(=O)[CH2:9][CH3:10].CC(O)=O.[Br:22]Br>O>[Br:22][C:12]1[C:13](=[O:15])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[N:1][C:8]=1[CH2:9][CH3:10]
Reactant: Nc1ccccn1
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)CC
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2ccccn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A solution of aminopyridine (32.6 g, 347 mmol), ethyl propionylacetate (50.0 g, 347 mmol) and AcOH (250 ml) were heated at reflux overnight. The solution was cooled to room temperature and was added additional 250 ml of acetic acid. The reaction was cooled in a water batch. The resulting solution was treated with 17.8 ml of bromine drop-wise over approximately 10 min. After stirring at room temperature for 2 hours. The precipitate was filtered. The solid was washed with ether two times and 40% ethyl acetate-hexanes once and dried in vacuum to give 31.5 g K2 as the first crop. The filtrate was concentrated to a small volume and the precipitate was filtered. The solid was washed with ether two times and 40% ethyl acetate-hexanes once and dried in vacuum to give 47.1 g of K2 as the second crop. Combined yield: 89.9% over two steps.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[C:11]([NH:14][C:15]1[NH:16][C:17](=O)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[C:11]([NH:14][C:15]1[N:16]=[C:17]([C:5]2[N:4]=[CH:3][NH:2][N:1]=2)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12]
Reactant: c1nc[nH]n1
Reactant: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1nc(-c2nc[nH]n2)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A suspension of 1,2,4-triazole (120 mmol) and phosphorus oxychloride (36 mmol) in dry acetonitrile (150 ml) was added to a stirred suspension of the 2-acetamido-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one of example 1 (12 mmol) and triethylamine (36 mmol) in dry acetonitrile (150 ml). The mixture was stirred at room temperature under nitrogen for 70 hours (or, alternatively, at 50° C. for 24 hours) and the yellow precipitate formed was filtered off, then successively washed with ethanol and ether, and further dried over P2O5 under vacuum. Solvents were evaporated in vacuo, then the crude residue was dissolved in dichloromethane and extracted with a diluted hydrochloric acid solution (HCl 0.01 N). The combined organic layers were dried over anhydrous MgSO4 and evaporated, thus providing the crude title compound in 72% yield, which was characterized by its mass spectrum as follows: MS (m/z): 350 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1.O>[CH2:32]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 11 h
Yield: 96 %

Procedure:
4.46 g (0.05 mole) of L-alanine was taken, 11.4 g (0.06 mole) of p-toluenesulfonic acid hydrate was taken, and 11.79 g (0.055 mole) of myristyl alcohol was taken as an alcohol. After 200 ml of benzene was added thereto as a solvent, these materials were stirred and mixed well. The resulting reaction mixture was heated at the reflux temperature of benzene to carry out the esterification reaction. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with benzene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7-15 hours. After being cooled to room temperature, the reaction mixture was poured into a separating funnel and treated with 200 ml of a mixture of 0.2N NaOH and 3M NaCl solutions. This treatment was repeated three times. Thereafter, the benzene layer was isolated and washed thoroughly with water. After washing with water, the benzene layer was isolated and dried overnight over anhydrous sodium sulfate. After drying, the benzene layer was filtered and the resulting benzene solution was evaporated to remove the solvent. Thus, there was obtained 13.7 g (96% yield) of purified free L-alanine myristyl ester in the form of an oily material.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.O>[Cl:9][C:10]1[N:15]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:13]=[CH:12][N:11]=1
Reactant: OCC(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride/60 percent oil dispersion (286 mg, 7.1 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethanol (675 mg, 6.7 mmol). The reaction mixture was stirred for 30 minutes, then it was then added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol). The solution was then allowed to stir overnight while warming to room temperature. The solution was diluted with H2O and extracted thrice with Et2O. The organics were combined, washed with brine, dried (Na2SO4) and filtered through silica gel, eluting with ether. The product was isolated as a semi-solid, 1.1 g, 5.2 mmol, 78 percent yield.
Reaction SMILES: Cl.Cl.[C:3]12([CH2:9][O:10][C:11]3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:8][CH:7]1[CH2:6][NH:5][CH2:4]2.[F:22][C:23]([F:34])([F:33])[C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26][CH2:25]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[F:22][C:23]([F:33])([F:34])[C@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]([N:5]2[CH2:6][CH:7]3[C:3]([CH2:9][O:10][C:11]4[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=4)([CH2:8]3)[CH2:4]2)=[O:31])[CH2:28][CH2:29]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OCC12CNCC1C2
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 1 using ethyl 3-(3-azabicyclo[3.1.0]hexan-1-ylmethoxy)picolinate dihydrochloride (EXAMPLE 88, Step 2) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([NH:10][S:24]([CH2:23][CH2:22][N:13]3[C:12](=[O:11])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:21])(=[O:25])=[O:26])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCN(C2CC2)CC1

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-cyclopropyl-piperidin-4-yl)-amide was prepared by an analogous procedure as described for example 1 i) starting from 154 mg (1.1 mmol) 1-cyclopropyl-piperidin-4-ylamine (obtainable as described in EP 1479676) and 300 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as a colorless foam.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.O[CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Diethyl azodicarboxylate (218 mg, 1.25 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (159 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), 4-hydroxy-1-methylpiperidine (115 mg, 1 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in methylene chloride (5 ml) cooled at 5° C. under nitrogen. The mixture was stirred for 1 hour at ambient temperature, the solvent was removed by evaporation and the residue was partitioned between 2M hydrochloric acid and ether. The aqueous layer was separated, adjusted to pH9 with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified on neutral alumina eluting with- methylene chloride/methanol (97/3). The purified product was triturated with ether, collected by filtration and dried to give 4-(4chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline (180 mg, 79%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[CH:22][CH:21]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccncc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-pyridin-4-yl-ethylamine and DIEA to give 2-(2-pyridin-4-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 361 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(CC)CC>C(Cl)Cl>[CH3:9][S:10]([O:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H](C)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)COS(C)(=O)=O
Yield: 102.1 %

Procedure:
A solution of methyl 3-hydroxy-2-(S)-methylpropanoate (35 g, 295 mmol) in 830 mL of CH2Cl2, under N2 atmosphere, was cooled to -60° C. With rapid stirring, methanesulfonyl chloride (24 mL, 310 mmol) was added, followed by Et3N (50 mL, 354 mmol) over 90 s. As the addition ended, a heavy white precipitate formed which stopped the magnetic stirring. The cold bath was removed and the reaction allowed to reach r.t. The reaction mixture was poured into aq 25% NH4OAc. After separation, the organic phase was dried over MgSO4 and evaporated to give the title compound as a colorless oil (59.1 g, 102%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.Cl[C:18]1[CH:19]=[CH:20][N:21]=[C:22]2[C:27]=1N=[CH:25][C:24]([O:28][CH3:29])=[CH:23]2.[CH3:30]C(O)C>>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:1][CH2:2][CH2:3][N:4]3[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:5]3)=[CH:19][CH:20]=[N:21]2)=[CH:30][CH:25]=1
Reactant: CC(C)O
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: NCCn1nc(-c2ccccc2)ccc1=O
Product: COc1ccc2c(NCCn3nc(-c4ccccc4)ccc3=O)ccnc2c1
Temperature: 150 °C

Procedure:
A mixture of 2-(2-aminoethyl)-6-phenylpyridazin-3(2H)-one (60 mg, 743 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (55 mg, 282 μmol) in iPrOH (2 mL) was heated to 150° C. for 15 min under microwave. The mixture was filtered and the filtrate was chromatographed on silica with 2-5% (2N NH3-MeOH) in CH2Cl2 to give the product as a white solid (60 mg). MS (ESI pos. ion) calc'd for C21H19N5O2: 373.1; found 374.2 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.81-3.89 (m, 2 H) 3.92 (d, J=1.37 Hz, 3 H) 4.64 (t, J=5.48 Hz, 2 H) 6.54 (dd, 1 H) 7.03 (dd, J=9.78, 1.57 Hz, 1 H) 7.10 (s, 1 H) 7.39-7.48 (m, 4 H) 7.66 (dd, J=9.59, 1.56 Hz, 1 H) 7.70-7.79 (m, 2 H) 8.38 (t, 1 H) 8.46 (dd, 1 H).
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>ClCCl>[CH3:24][S:25]([O:14][CH2:13][C:10]1[CH2:9][CH:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[O:12][N:11]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1=NOC(CN2CCOCC2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1=NOC(CN2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-(morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-3-yl]methanol (0.38 g) in dichloromethane was added dropwise diisopropylethylamine (0.33 mL) and methanesulfonyl chloride (0.15 mL). The resulting solution was stirred at room temperature for 3 h and treated with water. The layers were separated and the organic layer was dried (Na2SO4) en concentrated in vacuo to afford [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methanol methanesulfonate, 0.52 g (˜100%). Rf 0.63 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[CH:25]=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([C:29]([OH:31])=O)[C:21]=3[CH:20]=[CH:19][C:18]2=[O:32])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.F[P-](F)(F)(F)(F)F.[N:54]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:58]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][N:8]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[C:22]([C:29]([NH:54][CH3:58])=[O:31])[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[CH:20]=[CH:19][C:18]4=[O:32])[CH2:11][CH2:10]3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
463 mg of 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-5-carboxylic acid and 144 mg of methylamine hydrochloride were dissolved in 10 mL of N,N-dimethylformamide. To the mixture, 706 mg of (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and 0.47 mL of N,N-diisopropylethylamine were added and stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with a mixture of ethyl acetate: toluene=5:1. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 401 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale brown foam.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]2[C:6](=[O:8])[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:17]2=[S:18])[CH:15]=1
Reactant: CC(C)NCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C(C)C)C1=S
Yield: 54.7 %

Procedure:
A mixture of the crude N-isopropyl glycine (21.2 g), 5-chloro-2-methylphenylisothiocyanate (18.3 g), triethyl amine (21.0 g) and chloroform (300 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2×300 mL), then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (15.4 g) as a peach solid, m.p. 142°-144° C. Anal. Calcd. for. C13H15Cl N2O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+FAB, [M+H]+) m/z 283/285.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[C:23]1([S:29][CH2:30][C:31]([NH2:33])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:30]([S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:31]([NH2:33])=[O:32]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NC(=O)CSc1ccccc1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C(Sc1ccccc1)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (-70° C.) solution of 80.72 g (0.349 mole) of 2-amino-5-chlorobenzophenone in 1.5 liter of methylenechloride, under nitrogen atmosphere, was added 39.1 g (0.360 mole) of t-butyl hypochlorite in 100 ml of methylene chloride. After stirring for 10 min, a solution of 59.1 g (0.354 mole) of α-(phenylthio)acetamide in 1.5 liter of tetrahydrofuran was added. The mixture was stirred for 1.25 hr at -65° C., 37.5 g (0.371 mole) of triethylamine was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water and the organic layer was dried over anhydrous sodium sulfate. The volume of solution was reduced in vacuo and yellow solid precipitated which when recrystallized from acetonitrile was a yellow crystalline solid, m.p. 190°-191° C.(d). Analysis: Calculated for C21H17N2O2SCl: C,63.55; H,4.32; N,7.06. Found: C,63.62 ; H,4.29; N,7.08.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3].[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:1]([NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:27]3[N:26]([CH3:25])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: CCCNC(=O)C1(CCCCN2CCN(c3nc4ccccc4n3C)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-propylamide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.Cl[CH2:14][C:15]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:16].O>CN(C)C=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([N:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:15](=[O:16])[CH2:14][N:6]2[C:2](=[O:12])[C:3]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]3[C:5]2=[O:7])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CCl)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
tert-Butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido] acetate may be prepared in the following manner: phthalimide potassium salt (7.5 g) is added to a solution of tert-butyl 2-[2-chloro-N-(3-methoxyphenyl)acetamido]acetate (6.3 g) in dimethylformamide (100 cc). The mixture is stirred at a temperature in the region of 100° C. for 5 hours and then poured into water (1000 cc). The insoluble product is separated by filtration, washed with water (3×60 cc) and dried in the air. After recrystallisation in diisopropyl ether, tert-butyl 2-[N-(3-methoxyphenyl)-2-phthalimidoacetamido]acetate (6.7 g), m p 138° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16].[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>C1(C)C=CC=CC=1.CCOCC>[OH:16][C:15]([C:2]1[CH:7]=[CH:6][C:5]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][N:3]=1)([CH3:17])[CH3:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)O)nc1
Temperature: -50 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2,5-dibromopyridine in toluene (5 ml/mmol) at −78° C., was added n-butyllithium 2.5M in hexanes (1 eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (1 eq) was added, and the mixture was warmed to −50° C. and became a brown solution. After cooling down to −78° C., more n-butyllithium (1 eq) was added along with ether (2 ml/mmol). After stirring in the cold for a further hour, tributyltin chloride (1.1 eq) was added and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 2-(1-Hydroxy-1-methylethyl)-5-tributylstannylpyridine compound as a colorless liquid.