Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.70 g), methyl 2-(2-hydroxyphenyl)acetate (0.33 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.50 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: CC1(C)C2CC1CC=C2C=O.CN(C)[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].[C:23]12([CH2:33][CH2:34][C:35]3[NH:39][C:38]([C:40]4[CH:41]5[CH2:46][CH:43]([CH2:44][CH:45]=4)[C:42]5([CH3:48])[CH3:47])=[N:37][C:36]=3[C:49](O)=[O:50])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.Cl.C[O:54][C:55](=[O:63])[C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([NH2:62])[CH:57]=1>>[CH2:16]([O:17][C:49]([C:36]1[N:37]=[C:38]([C:40]2[CH:41]3[CH2:46][CH:43]([CH2:44][CH:45]=2)[C:42]3([CH3:48])[CH3:47])[NH:39][C:35]=1[CH2:34][CH2:33][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)=[O:50])[C:15]1[CH:14]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]12([CH2:33][CH2:34][C:35]3[NH:39][C:38]([C:40]4[CH:41]5[CH2:46][CH:43]([CH2:44][CH:45]=4)[C:42]5([CH3:48])[CH3:47])=[N:37][C:36]=3[C:49]([NH:62][C:58]3[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=3)[C:55]([OH:54])=[O:63])=[O:50])[CH2:32][CH:27]3[CH2:26][CH:25]([CH2:31][CH:29]([CH2:28]3)[CH2:30]1)[CH2:24]2
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC1(C)C2CC=C(c3nc(C(=O)O)c(CCC45CC6CC(CC(C6)C4)C5)[nH]3)C1C2
Reactant: CN(C)c1ccccc1C=O
Agent: CC1(C)C2CC=C(C=O)C1C2
Agent: Cl
Product: CC1(C)C2CC=C(c3nc(C(=O)Nc4cccc(C(=O)O)c4)c(CCC45CC6CC(CC(C6)C4)C5)[nH]3)C1C2
Product: CC1(C)C2CC=C(c3nc(C(=O)OCc4ccccc4)c(CCC45CC6CC(CC(C6)C4)C5)[nH]3)C1C2

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 70, step a, with the modification that (1R)-(−)-myrtenal was used in instead of 2-dimethylamino-benzaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester hydrochloride using essentially the same procedure as in Example 52, step a. Deprotection was carried out following essentially the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d4-MeOH) 8.36 (1H, t), 7.90 (1H, ddd), 7.75 (1H, dt), 7.42 (1H, t), 6.30 (1H, m), 3.02 (1H, dt), 2.99 (2H, m), 2.57 (1H, m), 2.49 (2H, dd), 2.19 (1H, m), 1.95 (3H, s), 1.71 (6H, m), 1.60 (6H, d), 1.42 (2H, m), 1.40 (3H, s), 1.26 (1H, d), 0.90 (3H, s) was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.39; H, 7.98; N, 7.58%. C39H56N4O8.2.2 H2O requires: C, 62.55; H, 8.14; N, 7.48%.
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[S:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11][S:25]1
Reactant: ClCC[NH2+]Cc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1Cc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:12][C@@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C:9]2=[O:16])=[N:4][N:5]([CH3:7])[CH:6]=1.[C:17]([O:21][C:22]([N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:25]1[CH:30]=[C:29]([C:31]2[O:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:28]=[CH:27][N:26]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:15][N:13]([CH3:14])[C@@H:11]1[CH2:12][N:8]([C:3]2[C:2]([NH:1][C:36]([C:34]3[N:35]=[C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([N:24]([CH2:39][C:40]([F:42])([F:41])[F:43])[C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:30]=4)[O:32][CH:33]=3)=[O:37])=[CH:6][N:5]([CH3:7])[N:4]=2)[C:9](=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Reactant: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.3 %

Procedure:
To a solution of (4S)-1-(4-amino-1-methyl-1H-pyrazol-3-yl)-4-(dimethylamino)pyrrolidin-2-one (69.9 mg), 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylic acid (146 mg) and HATU (143 mg) in DMF (1.57 mL) was added diisopropylethylamine (0.082 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (63.7 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:32][C:33]([NH2:35])=[NH:34])=[N:11][CH:10]=1.[H-].[Na+].ClC1[C:48]2[C:43](=[CH:44]C=C(S(NC3C=C(C=CC=3)C(OC(C)(C)C)=O)(=O)=O)C=2)[C:42](Cl)=CN=1.O>CS(C)=O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([O:28][C:43]([CH3:48])([CH3:44])[CH3:42])=[O:27])(=[O:20])=[O:21])=[CH:16][CH:17]=2)[C:12]([NH:32][C:33]([NH2:35])=[NH:34])=[N:11][CH:10]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
3-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}benzoic acid trifluoroacetate ##STR11## Guanidine hydrochloride (140 mg, 1.47 mmol) was added in one portion to a suspension of NaH (44 mg, 80% dispersion by wt in mineral oil, 1.47 mmol) in DMSO (4.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of tert-butyl 3-{[(1,4-dichloro-7-isoquinolinyl)-sulphonyl]amino}benzoate (280 mg, 0.59 mmol) in DMSO (2.0 mL) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was poured into water (50 mL), extracted with EtOAc (×3) and the combined organic phase was then evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 95:5:0.5) as eluant to give tert-butyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}benzoate (64 mg, 0.13 mmol) as a tan solid.
Reaction SMILES: [C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:13]=2)=[N:8]1)([O:3]CC)=[O:2].C(O)(=[O:32])C>C(O)C.[OH-].[Na+].O>[C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:32])[CH:13]=2)=[N:8]1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cn1nnc(-c2cccc(OCc3ccc4ccccc4n3)c2)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1nnc(-c2cccc(OC(=O)c3ccc4ccccc4n3)c2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1.3 g of 2-carbethoxymethyl-5-[3-(2-quinolylmethyloxy)phenyl]tetrazole in 5 ml ethanol and 40 ml of 1N NaOH was stirred at 70° C. for 4 hours. It was cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 1.0 g product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[N:14]#[C:15][NH2:16].[CH:17](OCC)(OCC)OCC>>[C:15]([NH:16][CH:17]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1)#[N:14]
Reactant: N#CN
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(-c2ccccn2)cc1
Product: N#CNC=Nc1ccc(-c2ccccn2)cc1
Temperature: 150 °C
Yield: 61.8 %

Procedure:
A mixture of 2-(4-amino-phenyl)-pyridine (3.1 g), cyanamide (0.8 g) and triethyl orthoformate (3.6 g) was heated at 150° C. for a few minutes. The product which crystallized out was filtered off, washed with ethanol and dried to give 2.5 g of the title compound; M.p. 150°-151° C.
Reaction SMILES: OC[C:3]1[C:4]([CH2:13]O)=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.S(Cl)([Cl:17])=O.Cl[CH2:20][Cl:21]>>[Cl:17][CH2:13][C:4]1[C:3]([CH2:20][Cl:21])=[CH:8][N:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(C(F)(F)F)cc1CO
Reactant: ClCCl
Product: FC(F)(F)c1cc(CCl)c(CCl)cn1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a room temperature suspension of 2.5 mmol (5-Hydroxymethyl-2-trifluoromethyl-pyridin-4-yl)-methanol (CAS: 765298-25-7) in 3 ml dichloromethane was added dropwise 12.5 mmol thionylchloride. After 1 hour, the reaction mixture was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow oil (66% yield). MS (m/e): 243.0 (M−H, 100%)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH2:16][CH3:17])[CH2:5]1)=[N+]=[N-].[CH:18]1([S:21](Cl)(=[O:23])=[O:22])[CH2:20][CH2:19]1>CCO.[OH-].[OH-].[Pd+2]>[CH:18]1([S:21]([NH:1][C@@H:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH2:16][CH3:17])[CH2:5]2)(=[O:23])=[O:22])[CH2:20][CH2:19]1
Reactant: CC[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)C1CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
To a slurry of 20 wt % Pd(OH)2 on C (0.044 g, 0.062 mmol) in EtOH (30 mL) was added a solution of (2R,4S)-tert-butyl 4-azido-2-ethylpyrrolidine-1-carboxylate (1.5 g, 6.2 mmol, synthesized as described in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31, 1598-1611) in EtOH (10 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. The reaction mixture was stirred for about 4 h at ambient temperature and then was filtered and concd in vacuo. The residue was dissolved in pyridine (30 mL) and cyclopropanesulfonyl chloride (1.05 g, 7.49 mmol) was added. The reaction mixture was stirred for about 15 h at ambient temperature and then was partitioned between EtOAc (50 mL) and saturated aqueous CuSO4 (50 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concd in vacuo, and purified by chromatography on silica gel (80 g) eluting with 20-80% EtOAc in heptane to provide (2R,4S)-tert-butyl 4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95 g, 48%) as an oil: LC/MS (Table 1, Method a) Rt=2.12 min (ELSD); MS m/z: 319 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[C:22]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[CH2:11][CH2:10][N:9]2[CH2:29][C:30]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Reactant: COc1ccc(OC)c2c1CCNC2C(c1ccccc1)c1ccccc1
Product: COc1ccccc1CNC(=O)CN1CCc2c(OC)ccc(OC)c2C1C(c1ccccc1)c1ccccc1

Procedure:
prepared by reaction of 1-(Diphenyl-methyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzylamine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:29][N:30]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and the mixture was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After reaction completion, water was added and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the title compound (0.07 g, 70%) LCMS: 448.25 (M+1)+; HPLC % 98.34 (@254 nm) (Rt; 4.578; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.11 (s, 1H), 8.05 (t, 1H), 7.80 (s, 1H), 7.29 (s, 1H), 7.09 (s, 1H), 5.85 (s, 1H), 4.26 (d, 2H, J=3.2 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.69 (m, 2H), 1.60 (m, 2H), 1.42-1.49 (m, 4H). [3H merged in solvent peak].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1.[Br:13]Br>C(O)(=O)C>[BrH:13].[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[C:8]=2[Br:13])[N:3]=1
Reactant: Cc1cnc2cc(N)ccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1cnc2c(Br)c(N)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.4 %

Procedure:
To a solution of 2-methyl-6-aminoquinoxaline (15.8 g) in acetic acid (150 mL) was added dropwise a solution of bromine (15.88 g) in acetic acid (11 mL) at 0° C. After the addition, the reaction solution was stirred at 0° C. for one hour, and the precipitates were collected by filtration, washed with ether, and dried to give 2-methyl-6-amino-5-bromoquinoxaline hydrobromide (29.86 g, 94%), which was neutralized to give 2-methyl-6-amino-5-bromoquinoxaline.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][N:28]4[CH2:29][CH2:30][CH2:31][C:27]4=[O:26])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)CN1CCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4CCCC4=O)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 5-(3,4-di methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 0.24 g of (2-oxo-pyrrolidin-1-yl)acetyl chloride and 0.5 ml of triethyl amine in 50 ml of dichloromethane is stirred for 30 min and washed subsequently with aqueous sodium carbonate. After drying over magnesium sulphate the solvent is evaporated and the residue purified by column chromatography [silica, ethyl acetate/methanol:6:1 (Vol/Vol)]. Crystallized from diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28]C)=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([OH:28])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCOCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylate (100 mg) in methanol (20 mL) was added sodium hydroxide (40 mg, 1.00 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with hydrochloric acid (3 N) and the product was precipitated to afford 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (52 mg).
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(C1C=CC(C2C=CC(OC(CCC)C(O)=O)=CC=2)=CC=1)#N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCC1COc2cscc2O1
Agent: CCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
2.20 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 12.9 mmol; 10.3 mmol based on the main component EDT-methanol), 2.10 g (10.2 mmol) of N,N′-dicyclohexylcarbodiimide and 1 spatula tip of 4-(dimethylamino)pyridine are dissolved in 80 ml of CH2Cl2 and cooled in an ice bath. 3.00 g (10.2 mmol) of [(4′-cyano-1,1′-biphenyl-4-yl)oxy]valeric acid (see formula) are added a spatula at a time to the cold (0° C.) solution while stirring. Remaining [(4′-cyano-1,1′-biphenyl-4-yl)oxy]valeric acid is dissolved in 20 ml of CH2Cl2 and added to the reaction. After 1 hour, the reaction is continued at room temperature. After a further 48 hours, the colourless precipitate formed (N,N′-dicyclohexylurea) is filtered off. The clear, colourless solution is washed in succession with 3×75 ml of 1 N HCl, 3×75 ml of saturated NaHCO3 solution and 3×75 ml of saturated NaCl solution. The organic phase is dried over MgSO4, the desiccant is filtered off and the solvent is removed on a rotary evaporator. This gives 4.70 g of crude product.
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[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:35](C(C)C)C(C)C)C.[N:42]1[CH:47]=[CH:46][C:45](N)=[CH:44][CH:43]=1>ClCCl>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[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:35][C:44]5[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccncc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2cccnc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A mixture of 0.050 g (0.11 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-yl-amino)-3-methoxy-benzoic acid (I-22), 0.048 g (0.12 mmole) of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, 0.037 g (0.28 mmole) of ethyldiisopropyl amine, 0.016 g (0.17 mmole) of pyridine-4-ylamine and 0.5 ml of dichloromethane was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 0.5 ml of methanol, and then precipitated by the addition of water. The residue was washed three times with water and then purified by chromatography on reverse phase silica gel, eluting with acetonitrile-water to give 0.01 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-methoxy-N-pyridin-3-yl-benzamide (I-130)