Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: Cc1cccnc1CCl
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1ccn(CCc2ccc(CO)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 472 mg (2.65 mmol) 2-chloromethyl-3-methyl-pyridine and 845 mg (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:14][S:15](O)(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:14][S:15][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC)c(SCl)c1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 4-methoxybenzoate (15.7 g; 87.2 mmol) in CCl4 (60 ml) was cooled to −15° C., and chlorosulfonic acid (17.5 ml; 263 mmol) was added dropwise over a period of 15 min, resulting in a temperature increase to −10° C. After the addition had ended, the reaction mixture was stirred at room temperature for 2 h and then heated at 50° C. until no more starting material could be detected by thin-layer chromatography. With ice-cooling and vigorous stirring, the reaction mixture was added to a suspension of ice (50 g) in CCl4 (100 ml). The mixture was stirred vigorously for 3 min. The organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with saturated NaCl solution (3×), dried over Na2SO4 and concentrated. Trituration of the oily brown residue with diethyl ether resulted in 5c precipitating as a crystalline white solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][OH:8].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[S:35]([CH2:2][CH2:3][N:4]([S:9][C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH:7]([S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])[OH:8])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCN(CCC(O)S(=O)(=O)c2ccc(C)cc2)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
N-(2-Hydroxyethyl)-N-tritylsulfenyl-3-amino-1-propanol (5.0 g, 12.64 mmol) is dissolved in pyridine (100 mL) and cooled to 0° C. p-Toluensufonylchloride (2.65 g, 13.9 mmol) is dissolve in CH2Cl2 (50 mL) and added to the reaction mixture at 0° C. via dropping funnel. The reaction is monitored by TLC to completion. The reaction mixture is concentrated in vacuo and the resultant residue is dissolved in EtOAc and washed with H2O (3×50 mL) and brine (2×50 mL). The EtOAc is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography using EtOAc/hexanes as eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: C1C=CC=CC=1.[CH:7]([N:10]1[CH2:13][CH:12](CS([O-])(=O)=O)[CH2:11]1)([CH3:9])[CH3:8].[Na].[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]#[N:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1(C)C=CC=CC=1>[C:29]1([C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH:12]2[CH2:13][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:11]2)[C:27]#[N:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)N1CC(CS(=O)(=O)[O-])C1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h

Procedure:
The benzene solution of 1-isopropyl-3-azetidinylmethane sulfonate was added dropwise to the stirred refluxing toluene mixture containing the sodium salt of diphenylacetonitrile and refluxing continued for 1.5 hours after addition. The cooled reaction mixture was treated with water, the layers separated, and the organic layer extracted with dilute hydrochloric acid and water. The combined extracts were basified using dilute sodium hydroxide and the base insoluble material extracted with chloroform. The dried extract was concentrated and the residual material was recrystallized from isooctane. The α,α-diphenyl-α-(1-isopropyl-3-azetidinyl)acetonitrile weighed 142 g. (55%) and melted at 93°-95° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)c1ccc(S)cc1
Reactant: Nc1ncccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(Sc2cccnc2N)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-isopropylbenzenethiol (2.288 g), 3-bromopyridin-2-amine (2.0 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.669 g), tris(dibenzylideneacetone)dipalladium(0) (0.529 g) and DIEA (7.47 mL) in toluene (57.8 mL) was stirred overnight under a nitrogen atmosphere at 120° C. The reaction mixture was added to water, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2508 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N+:7]([O-:33])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]=1[CH3:19]
Reactant: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2ncccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[N+]1([O-])C(C)=C(Cc2ccc(Cl)cc2Cl)c2ncccc21
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate (400 mg) in chloroform (6 ml) was added m-chloroperbenzoic acid (462 mg) at room temperature, and the mixture was stirred overnight. The reaction mixture was subjected to flash silica gel chromatography (silica gel, 40 ml, eluted with ethyl acetate and then with ethyl acetate-methanol=10-1), and crystallized from ether to give the objective compound (417 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]2[CH:26]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:26][CH:14]2[N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:16](=[O:18])[O:17][CH:13]2[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3[N+](=O)[O-])=CC21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3N)CC21
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of (+/−)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in methanol and ethyl acetate (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.). The resulting mixture was stirred under H2 atmosphere for 6 hours. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (87%), which was used in the next step without further purification. LC/MS (m/z): MH+=334.1, Rt=0.51.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:7]([CH3:32])[N:6]=1.[H-].[Na+].CC(N(C)C)=O.[Br:41][C:42]1[CH:43]=[N:44][C:45](Cl)=[N:46][CH:47]=1>O1CCCC1.O>[Br:41][C:42]1[CH:43]=[N:44][C:45]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[N:7]([CH3:32])[N:6]=2)=[N:46][CH:47]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCO)nn2C)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc(C)cc3)c(OCCOc3ncc(Br)cn3)nn2C)cc1
Reaction time: 0.02 h
Yield: 80.5 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-pentyl)benzenesulfonamide (Example 8) (270 mg) in tetrahydrofuran (4 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 50 mg) and the mixture was stirred for 1 minute. To the mixture was added dimethyl acetamide (0.5 ml) followed by 5-bromo-2-chloropyrimidine (171 mg). The mixture was stirred for 2 hours at room temperature and then diluted with water (20 ml) and extracted with ether (2×20 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (35 g) eluted with hexane:ethyl acetate (2:1 to 1:2) to yield the title compound as an orange oil (292 mg).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[C:43](Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[C:43]([O:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution of pyridine (2.4 ml.) in dry tetrahydrofuran (5 ml.) was added to a stirred solution of diphenylmethyl 3-hydroxymethyl-7β-(thien-2-yl)acetamido-ceph-3-em-4-carboxylate (3.12 g) and pivaloyl chloride (7.2 g) in dry tetrahydrofuran (150 ml) at 20°. The solution was stirred at 20° for 16 hours, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with sodium bicarbonate solution, 2 N-hydrochloric acid, sodium bicarbonate solution, water and brine. The dried solution was concentrated under reduced pressure to give a solid residue that was triturated with ether to give the title ester (2.7 g; 75%), [α]D +5.1 (c 1.4, CHCl3), λinflex. (ethanol) 235 (ε14,100), 257 (ε8,300) and 263 nm. (ε8,050), λmax. (CHBr3) 1787 (β-lactam), 1722 (ester), 1680 and 1510 cm.-1 (CONH) τ (CDCl3) values include 8.81 (singlet; C(CH3)3).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([F:22])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)=[CH:8]2.[NH2:24][NH2:25]>CO>[F:22][C:6]1[C:5]([CH2:4][C:3]([NH:24][NH2:25])=[O:2])=[C:14]([F:15])[CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[CH:10]=[N:11]2
Reactant: COC(=O)Cc1c(F)cc2ncc(-c3cnn(C)c3)cc2c1F
Reactant: NN
Solvent: CO
Product: Cn1cc(-c2cnc3cc(F)c(CC(=O)NN)c(F)c3c2)cn1
Temperature: 55 °C
Yield: 83.7 %

Procedure:
To a 40 ml vial was added methanol (12 mL), [5,7-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]-acetic acid methyl ester (508 mg, 1.6 mmol) and hydrazine anhydrous (4 eq., 6.4 mmols). After 1 hour at 55° C. a second portion of hydrazine (4 eq., 6.4 mmol) was added and the reaction heated at 55° C. for a further 1 hour. The reaction mixture was cool down to room temperature, filtered and washed with cold methanol. The product was dried to return the title compound as a white solid (425 mg, 83% yield). MS: m/z 318.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C:2]2[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Nc1ccc[nH]c1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]cccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-aminopyridin-2(1H)-one (99 mg, 0.90 mmol), 2,4,5-trichloropyrimidine (165 mg, 0.90 mmol, 1 equiv.) and NaHCO3 (76 mg, 0.90 mmol, 1 equiv.) in a mixture of MeOH (6 mL) and H2O (3 mL) was stirred at room temperature for 24 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)pyridin-2(1H)-one; ESMS m/z 257.0 (M+H+).
Reaction SMILES: N[C:2]1C=C(Br)C=CC=1C(OC)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.N1(C2CCCCCCCCCC2)CCCNCCCCCC1.O>CN(C=O)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: C1CCCCCC(N2CCCCCCNCCC2)CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Methyl 2-amino-4-bromobenzoate. To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water (2×), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: Br[CH:2](C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[NH4+:15]>>[NH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(Br)CCCCCCCC(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: NCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9-bromodecanoic acid (2.0052 gr, 8.46 mmol) was added to a round bottom flask containing 80 mL of aqueous ammonium hydroxide (25% NH3). The resulting mixture was stirred for 24 hours at room temperature, after which the aqueous solution was evaporated under reduced pressure, resulting in product 8a as a white solid at quantitative yield. 1H-NMR (200 MHz, CD3OD): 1.25-1.4 (m; 8H), 1.5-1.7 (m; 4H), 2.23 (t; J=7.31 Hz; 2H), 2.87 (t; J=7.45 Hz; 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]1[NH:16][C:14](=[S:15])[NH:13][CH2:12]1>C(#N)C>[BrH:7].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:15][C:14]2[NH:16][CH2:11][CH2:12][N:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: S=C1NCCN1
Reactant: Fc1cc(Cl)ccc1CBr
Solvent: CC#N
Product: Br
Product: Fc1cc(Cl)ccc1CSC1=NCCN1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of 4-chloro-2-fluorobenzylbromide (0.223 g, 1.0 mmol) and N,N′-ethylene thiourea (0.102 g, 1.0 mmol) in acetonitrile (4.5 ml) was heated for 10 min to 110° C. by microwave irradiation. After cooling down to room temperature a solid precipitated that was removed by filtration and washed with ether. It was obtained 260 mg (80%) of a white solid; MS (ISP): 245.0; 247.0 ([M+H]+.).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][C:27](=O)[CH3:28].O>C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH:27]([CH:28]1[O:4][CH2:1][CH2:2][O:3]1)[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: CC(=O)Cc1c[nH]c2ccc(Cl)cc12
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1c[nH]c2ccc(Cl)cc12)C1OCCO1
Reaction time: 3 h

Procedure:
38g (0.61 mole) of ethylene glycol and 1.4 g of paratoluene sulphonic acid are added to 6.35g of 5-chloro-3-(2-oxopropyl)indole dissolved in 320 ml of anhydrous benzene. This mixture is brought to reflux and held thereat for 3 hours, the water formed being separated. The reaction mixture is dissolved in an aqueous solution of sodium bicarbonate and filtered to eliminate the insoluble material. The organic phase is decanted, dried and concentrated. The product obtained is recrystallised from ethanol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=3[N:7]=2)[CH2:2]1.Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[Cl:24][C:23]1[C:18]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[NH:10][C:9]4[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=4[N:7]=3)[CH2:2]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccnc1Br
Reactant: N#Cc1ccc2[nH]c(C3CCNC3)nc2c1
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]c(C3CCN(c4ncccc4Cl)C3)nc2c1
Temperature: 130 °C
Yield: 13.5 %

Procedure:
The mixture of 2-pyrrolidin-3-yl-1H-benzoimidazole-5-carbonitrile (120 mg, 0.57 mmol), 2-bromo-3-chloro-pyridine (109 mg, 0.57 mmol) in pyridine was heated at 130° C. by microwave for 45 mins. Then it was concentrated to give the crude product and purified by column chromatography and followed by preparative HPLC to afford pure product (25 mg, 18%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:22]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(F)cc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 34.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 3′-fluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (90 mg, 0.28 mmol) as described in Example 7 part g), affording 3′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (30 mg, 35%). δH (360 MHz, CDCl3) 7.32-7.36 (1H, m), 7.41-7.44 (1H, m), 7.50-7.59 (3H, m), 7.64 (1H, d, J 4.6), 7.72 (1H, td, J 7.7 and 1.4), 7.85 (1H, dd, J 7.7 and 0.7), 7.90 (1H, d, J 8.8), 8.75 (1H, d, J 8.8), 9.30 (1H, d, J 4.2). m/z (ES+) 394 [MH]+.
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].[C:17]([O-])([O-])([O:19][CH2:20][CH3:21])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([N:1]=[C:17]([O:19][CH2:20][CH3:21])[CH3:18])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(C)([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(C)=Nc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A solution of 11.5 parts of 2-amino-5-chlorobenzophenone, 11.5 parts of ethyl orthoacetate and 6 volume parts of acetic acid in 100 volume parts of benzene is refluxed for 20 minutes, whereby 5-chloro-2-(1-ethoxyethylideneamino)-benzophenone are obtained as crystals. Recrystallization from methanol-water gives colorless needles melting at 62° to 63° C. Yield: 93%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:24]#[N:25].C(OCC)C.[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18]([C:24]#[N:25])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)CCO1
Reactant: N#C[Cu]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C#N)cc1[C@H]1CN(Cc2ccccc2)CCO1
Yield: 0.1 %

Procedure:
A solution of (2S)-4-benzyl-2-(5-bromo-2-methoxyphenyl)-morpholine (17.1 g, 47.2 mmol) and copper cyanide (6.35 g, 70.9 mmol) in 1-methyl-2-pyrrolidinone (140 ml) was stirred at 160° C. for 9 hours. Diethyl ether and 1N aqueous sodium hydroxide were added to the reaction mixture, and the solution was passed through Celite column. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (2S)-4-benzyl-2-(5-cyano-2-methoxyphenyl)-morpholine (10.1 mg, 69%) as a yellow oil.