Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:18]1([C:24]([CH:26]=O)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH3-]C#N.[Na+]>CO>[C:18]1([CH:24]([OH:25])[CH2:26][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.47.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]([SH:6])([CH3:5])[CH3:4])[CH3:2].[CH2:7]([P:9]([Cl:12])([Cl:11])=O)[CH3:8]>>[C:3]([SH:6]=[P:9]([Cl:12])([Cl:11])[CH2:7][CH3:8])([CH2:1][CH3:2])([CH3:5])[CH3:4]
Reactant: CCC(C)(C)S
Reactant: CCP(=O)(Cl)Cl
Product: CCC(C)(C)[SH]=P(Cl)(Cl)CC

Procedure:
In a manner similar to that of Example 1, 2-ethyl-2-propanethiol was reacted with ethylphosphonic dichloride to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][CH:13]=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>ClC1C=CC=CC=1Cl>[CH3:17][N:16]1[C:12]2[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[NH:1][C:18](=[O:19])[C:13]=2[N:14]=[CH:15]1
Reactant: Cn1cncc1-c1cc2ccccc2cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: Cn1cnc2c(=O)[nH]c3cc4ccccc4cc3c21
Temperature: 180 °C
Yield: 41.2 %

Procedure:
A mixture of 5-(3-amino-2-naphthyl)-1-methylimidazole (Preparation 17) (0.48 g, 2.14 mmol) and 1,1′-carbonyldiimidazole (0.42 g, 2.57 mmol) in o-dichlorobenzene (22 mL) was heated at 180° C. for 5 hours. The suspension was cooled to RT, filtered, and dried under vacuum, affording the title compound as a light yellow solid (0.22 g, 42%). 1H NMR (DMSO): 11.57 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.4, 1H), 7.89 (d, J=8.4, 1H), 7.84 (s, 1H), 7.53 (m, 1H), 7.46 (m, 1H), 4.30 (s, 3H). (ES m/z (M+H)+=250.08.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13](=O)[C:3]1=2.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CCO.O>[OH:17][N:16]=[C:13]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:11][CH2:12]1
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3ccccc31)CCC2=NO
Reaction time: 8 h

Procedure:
To a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (3.0 g) in 30 ml of 95% EtOH was added hydroxylamine hydrochloride (2.25 g) in 9 ml water followed by sodium acetate (4.4 g) in 9 ml water. The mixture was heated at reflux for 4 hours and thereafter an additional 1.1 gram of hydroxylamine hydrochloride in 5 ml water and 2.2 grams of sodium acetate in 5 ml water were added.. After an additional 2 hours of reflux, the mixture was allowed to stand at room temperature overnight. The material which precipitated was collected and recrystallized from 95% EtOH to give 1.9 grams of analytically pure material.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 48G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(c1cccnc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A toluene (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (200 mg, 0.662 mmol) obtained in Example 98, 5-(tert-butyldimethylsilyloxy)pentanol (288 mg, 1.32 mmol) and cyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol) was heated under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure, whereby the title compound (307 mg, 92%) was obtained as a colorless oil.
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:44]=[CH:43][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:18]3=[O:42])=[CH:14][CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>FC(F)(F)C(O)=O>[N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:42])=[CH:43][CH:44]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1SC(Cc2ccc(OCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCc3cn4ccccc4n3)cc2)S1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 3.0 g of 5-{4-(imidazo-[1,2-a]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethyl-thiazolidine-2,4-dione (prepared as described in Preparation 21) were reacted with 30 ml of trifluoroacetic acid for 1 hour. At the end of this time, the reaction mixture was freed from trifluoroacetic acid by distillation under reduced pressure. An aqueous solution of potassium carbonate and ethyl acetate were added to the residue, and the resulting precipitated insoluble material was collected by filtration, dried over anhydrous sodium sulfate and recrystallized from ethanol, to give 0.8 g of the title compound, melting at 197°-202° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([NH2:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:8]=[C:7]([C:9]#[N:11])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cc([N+](=O)[O-])n[nH]1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])n[nH]1

Procedure:
3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 19.2 mmol) in pyridine (30 mL) was treated with phosphorus oxychloride (5.9 g) and the resultant solution was stirred for 3 h at rt. The reaction mixture was diluted with ice, then extracted with DCM (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude 3-nitro-1H-pyrazole-5-carbonitrile, which was used directly in the next step without further purification. LC-MS (ESI) m/z 137 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30](OC)=[O:31])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:30]([C:26]2[S:27][CH:28]=[CH:29][C:25]=2[NH:24][CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[CH:14][CH:15]=2)=[O:31])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1sccc1NCc1ccnc2ccccc12
Reactant: Nc1cccc(I)c1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(I)c1)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3-iodoaniline (1.27 mL, 1 mmol) in anhydrous toluene (100 mL) in a pre-dried flask under N2 atmosphere was added trimethylaluminium (6.1 mL of a 2M solution in toluene, 12.0 mmol), and the resulting solution left to stir at rt overnight. Methyl 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate (3.0 g, 10 mmol) was then added and the mixture heated at reflux for 5 h. Upon cooling to rt, 100 mL of 2M NaOH was added and the mixture was stirred for 30 min. The solution was then partitioned over CH2Cl2 and the aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was treated with MeOH, sonicated for 2 min, and filtered. The solid was washed with MeOH to provide 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid (3-iodophenyl)amide as a brown powder. MS (ES): m/z 485.8 [M+1]. 1H NMR (DMSO-d6, 400 MHz): δ5.06 (d, J=5.4 Hz, 2H), 6.77 (d, J=5.6 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.37 (d, J=6.0 Hz, 2H), 7.60 (d, J=5.6 Hz, 1H), 7.66-7.69 (m, 2H), 7.78 (t, J=7.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.04-8.10 (m, 1H), 8.19 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H), 9.47 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: C=CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: CC(C)O
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 25 °C

Procedure:
2-Chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one, 4-amino-3-methoxy benzoic acid (1.2 equivalent), i-PrOH and conc. HCl (30 drops) were heated to 95° C. for 18 hours. A this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid in good yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.75 (m, 6 H) 1.85 (m, 2 H) 3.29 (s, 3 H) 3.73-3.97 (m, 2 H) 3.93 (s, 3 H) 4.94 (m, 1 H) 5.40-5.54 (m, 2 H) 6.05 (m, 1 H) 7.48-7.65 (m, 2 H) 8.09 (d, J=8.34 Hz, 1 H) 8.23 (s, 1 H) 9.51 (br. s., 1 H). [M+H] calculated for C23H26FN5O4, 456; found 456.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=3[CH3:21])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:22][CH2:23][CH3:24])([CH2:5][C:4]([OH:25])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)ccc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (0.959 g, 2.82 mmol) in THF/MeOH (7 mL/15 mL) was added 1 N NaOH (5.64 mL, 5.64 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (60 mL), dried over Na2SO4 and concentrated to provide 0.868 g (99%) of title compound as a white solid. 1H NMR (acetone-d6): 300 MHz δ 10.37 (bs, 1H), 7.35 (d, J=7.50 Hz, 1H), 7.03 (d, J=7.50 Hz, 1H), 4.05 (m, 2H), 3.08–2.91 (m, 4H), 2.54 (s, 3H), 2.09 (m, 2H), 1.45 (m, 1H), 1.03 (m, 1H), 0.84 (t, J=7.26 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([Cl:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1
Reaction time: 24 h
Yield: 99.6 %

Procedure:
A mixture of 27.2 g (0.2 moles) phenylacetic acid and 28 g (0.22 moles) oxalyl chloride in 150 ml methylene chloride were stirred for 24 hours. Excess reagent and solvent were removed by stripping to give 30.8 g of phenylacetyl chloride, which was used in step (b) without further isolation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])#[N:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:16][C:4]1[CH:5]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[N:13][CH:12]=[N:11][CH:10]=2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:23])#[N:18]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN(c1cncnc1)c1cc(N)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(c1cncnc1)c1cc(F)cc(NC(=O)c2cccc(C#N)c2)c1
Reaction time: 0.08 h
Yield: 26.2 %

Procedure:
Compound 32 (15 mg, 0.069 mmol, 1.0 eq) was dissolved in CH2Cl2 (0.5 mL) and DMAP (9.2 mg, 0.075 mmol, 1.1 eq) was added and the reaction stirred for 5 min. 3-Cyanobenzoyl chloride (11 mg, 0.066 mmol, 1.0 eq) was added and the reaction was stirred until determination of completion by LCMS. The reaction was diluted with CH2Cl2, washed with water (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6 mg (47%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.82 (s, 1H), 8.63 (s, 2H), 8.34 (s, 1H), (8.19 (d, J=8.0 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.44 (d, J=11.0 Hz, 1H), 7.22 (s, 1H), 6.79-6.73 (m, 1H), 3.34 (s, 3H); ES-MS [M+1]+: 348.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NCC(C)(C)C)n1
Yield: 51.5 %

Procedure:
The reaction of 4-chloro-2,6-bis(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 gives the title product in a yield of 51.5%, m.p.: 138°-140° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:32][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccc(Nc2cccnc2)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)c2cccnc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
190 mg of 4-[N-(3-pyridyl)amino]benzonitrile was dissolved in 5 ml of N,N-dimethylformamide, and 44 mg of 60% sodium hydride was added thereto under cooling with ice, followed by stirring at 40-50° C. for 30 minutes. Then, 273 mg of 4-benzyloxybenzyl chloride was added to the reaction mixture under cooling with ice, followed by stirring at room temperature for 2 hours. After the reaction mixture was poured into water, the product was extracted with chloroform. After the extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 234 mg of 4-[N-(4-benzyloxy-benzyl)-N-(3-pyridyl)amino]benzonitrile.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl[CH2:13][C:14](Cl)=[O:15].[OH-].[Na+]>C(O)C>[C:2]1([N:1]2[CH2:8][CH2:9][O:10][CH2:13][C:14]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: OCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1COCCN1c1ccccc1
Temperature: 38 °C

Procedure:
In a 26-liter tank, 1.65 kg (12.0 mol) of 2-anilinoethanol are dissolved at room temperature in 1.53 l of ethanol and subsequently admixed with 4.58 l of water with stirring. The solution is heated to 38° C. 4.07 kg (3.0 equivalents) of chloroacetyl chloride and 6.60 kg of 45% sodium hydroxide solution (6.2 equivalents) are then added simultaneously at an internal temperature of 38 to 43° C. within 60 to 80 minutes, so that the pH is kept between 12 and 12.5. The mixture is stirred at a pH of 12 to 12.5 for 10 minutes, then cooled to 2° C. and stirred at this temperature for 30 minutes. The precipitated product is filtered off and washed twice with 3.3 kg each time of demineralized water at 2° C. The moist product is dried to constant mass at 50° C. under reduced pressure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[C:15]([CH:25]=[O:26])=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C=O)c(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine in THF (0.1M) at 0° C. was added n-BuLi (1.1 eq.). The solution was stirred for 30 min and then was cannulated in a solution of commercially available 5-bromo-2-methoxypyridine in THF (0.1M) at −78° C. The resulting solution was stirred at −78° C. for 30 min then DMF (1.5 eq.) was added. Final reaction mixture was allowed to warm to 0° C. before it was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The organic extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[OH-].[Na+].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>O.O1CCCC1>[OH:6][CH:4]1[CH2:5][N:2]([C:17]([O:16][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (2 g, 18.26 mmol, 1.00 equiv) and sodium hydroxide (1.53 g, 38.25 mmol, 2.10 equiv) in water (10 mL) and tetrahydrofuran (25 mL) was added Cbz-Cl (3.27 g, 19.17 mmol, 1.05 equiv) dropwise with stirring at 0° C. over 30 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The mixture was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×40 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). Purification afforded 2.0 g (53%) of benzyl 3-hydroxyazetidine-1-carboxylate (50.2) as a light yellow liquid.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)[CH3:4])#[N:2].[OH-:22].[Na+]>>[O:21]=[C:19]1[CH2:18][C:17]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[S:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([CH3:4])[C:1]([NH2:2])=[O:22])=[CH:6][C:7]1=2
Reactant: [OH-]
Reactant: CC(C#N)c1ccc(Sc2ncccc2CC(=O)O)cc1
Agent: [Na+]
Product: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 150 °C
Reaction time: 1.08 h

Procedure:
The mixture of 101 mg of 2-[4'-(α-cyanoethyl)-phenylthio]-3-pyridylacetic acid and 2 g of polyphosphoric acid was stirred at 150° C. for 65 minutes. After cooling, to this was added ice-water and the mixture was neutralized with conc. sodium hydroxide solution and 3% sodium hydroxide solution, then was made alkaline therewith. The resulting mixture was extracted with ethyl acetate and the extract was washed with 3% sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 36 mg of yellow glutinous substance, which was chromatographed over silica gel, eluted with n-hexane/acetone (2/1) and there was obtained 25 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionamide as colorless glutinous substance. This was solidified with ethanol to give crystals having a melting point of 175°-180° C. These were recrystallized from ethanol to give crystals having a melting point of 190°-192.5° C.
Reaction SMILES: F[C:2]1[C:7]2[N:8](CC3C=CC4NC5C=CC=CC=5CCC=4C=3)[C:9]([CH2:11][CH2:12]C)=[N:10][C:6]=2[C:5]([CH3:30])=[CH:4][CH:3]=1.FC1C2NC(CCC)=[N:37]C=2C(C)=CC=1>>[CH2:11]([C:9]1[NH:8][C:7]2=[N:37][C:3]([CH3:2])=[CH:4][C:5]([CH3:30])=[C:6]2[N:10]=1)[CH3:12]
Reactant: CCCc1nc2c(C)ccc(F)c2n1Cc1ccc2c(c1)CCc1ccccc1N2
Reactant: CCCc1nc2c(C)ccc(F)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(7-Fluoro-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (370 mg, 92%) was obtained in the same manner as in step 1 of Example 1, using 4-fluoro-7-methyl-2-propylbenzimidazole (478 mg, 1.10 mmol), obtained in Reference Example 4, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH3:27])[CH:21]=1
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccc(Cl)c(C)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-chloro-3′-methylacetophenone.