Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH:11]=[C:12]([O:15][C@H:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C@@H:19]([NH2:26])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:26][C@@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[N:7][N:8]=4)[CH:11]=3)[CH2:17][CH2:18]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of Intermediate 75b (62.0 mg, 0.18 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 78.9 mg, 0.195 mmol), DIPEA (46.3 μL, 0.27 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (22 mg, 20%). LCMS (Method 5) Rt 4.30 min, m/z 605 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.79-2.15 (8H, m), 2.36 (3H, s), 3.49 (4H, m), 4.81 (1H, m), 5.51 (1H, t, J 4.5), 6.30 (1H, s), 7.03 (1H, dd, J 10.1, 2.2), 7.09 (1H, d, J 8.5), 7.25-7.40 (8H, m), 7.51 (1H, m), 7.83 (1H, m), 8.07 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:37](=[O:38])[C:31]2[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=2)[C:40]1=[O:39]
Reactant: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl-5-(2-benzothiophenyl)benzoxazole (120 mg, 0.32 mmol) and 1,2,4-benzenetricarboxylic anhydride (62 mg, 0.32 mmol) the title compound was obtained. (41 mg, 23%). 1H NMR (DMSO) δ 13.82(s, 1H), 8.46(dd, 1H), 8.38(d, 1H), 8.35(m, 2H), 8.18(d, 1H), 8.13(d, 1H), 8.00(d, 1H), 7.96(s, 1H), 7.85(m, 3H), 7.50(d, 1H), 7.40(m, 2H), 3.90(s, 3H). MS 547.2 m/z (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[C:29]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)(=[O:31])[CH3:30]
Reactant: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 2 h

Procedure:
To the compound of example 10 (0.57 g) and triethylamine (0.55 ml) stirred in dichloromethane (50 ml) was added acetyl chloride (0.154 ml) dropwise, at 0° C. After 2 h at 0° C., more acetyl chloride (0.154 ml) was added and the reaction mixture stirred for a further 16 h and allowed to attain room temperature. The organic phase was washed with water and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave the crude product (0.33 g) which was recrystallised from ethyl acetate-dichloromethane to give the title compound (0.24 g) as colorless crystals of mp 206°-208° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH:20]([SnH3])=[CH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[C:14]1([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C[SnH3]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indole (8.52 g, 25.3 mmol, Intermediate 44) was dissolved in dry toluene (20 mL) under an N2(g) atmosphere before vinylstannane (16.07 g, 50.7 mmol) and bis[triphenylphosphine)palladium(II) acetate (0.95 g, 1.3 mmol) was added. The reaction was heated to 110° C. for 16 h cooled the reaction mixture to RT and filtered the reaction mixture through a celite pad, and evaporated the solvent. Dissolved the obtained oil in acetonitrile and hexanes, separated the phases. Evaporated the acetonitrile phase and purified the obtained crude product by flash chromatography using 30% DCM in hexanes. Isolated 4.4 g of the desired product as a white solid, yield 62%. MS (ESI+) for C16H13NO2S m/z 284 (M+H)+.
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)c1nccc(N2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)c1N
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (S)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding (S)-3-amino-6-bromo-N-(4-(3-(tert-butyldimethyl-silyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: C(O[C:4]1([O:14]CC)[NH:8][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:5]12)C.Cl.[C:18](OCC)(=[O:20])[CH3:19]>O1CCCC1>[O:14]=[C:4]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:9])[N:8]1[CH2:19][CH:18]=[O:20]
Reactant: CCOC(C)=O
Reactant: CCOC1(OCC)NC(=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C

Procedure:
To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75° C. for 5 hrs, the solution was allowed to cool to RT, and ethyl acetate (100 mL) was added. The solution was extracted with saturated sodium carbonate solution (100 mL), brine (100 mL), and the organic layer was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1cncn1
Temperature: 25 °C
Yield: 72 %

Procedure:
138 g (2 mol) of 1,2,4-triazole were added in portions to 276.4 g (2 mol) of ground potassium carbonate and 269.2 g (2 mol) of α-chloropinacolin in 500 ml of acetone at room temperature, the internal temperature rising to the boiling point. The reaction mixture was stirred under reflux for 5 hours and then cooled to room temperature. It was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. After adding benzene, the oily residue crystallized. 240.8 g (72% of theory) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 62°-64° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:15][OH:16].C[O-].[Na+]>NO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10](=[N:15][OH:16])[NH2:11])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: N#CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: NC(C=Cc1ccc([N+](=O)[O-])cc1)=NO
Reaction time: 8 h

Procedure:
p-Nitrocinnamonitrile (8.12 g.) was added at 30° 35° to an anhydrous methanolic hydroxylamine solution (320 ml.) prepared by neutralising hydroxylamine hydrochloride (13.00 g.) with methanolic sodium methoxide. The solution was refluxed for 2.5 hr. and left overnight. Removal of the solvent and washing with water left the crude amidoxime, 7.07 g. (74%), m.p. 184-185° (decomp.). Recrystallisation of a sample from ethanol gave p-nitrocinnamamidoxime as yellow needles, m.p. 184° -186° , λmax. (EtOH) 235.5, 265, 344 nm, (ε 10020, 10000, 14800) (Found: C, 51.7; H, 4.7; N, 20.0. C9H9N3O3 requires C, 52.2; H, 4.4; N, 20.3%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[N:13]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12](=[O:24])[CH:11]1[CH3:25].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[N:13]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[C:12](=[O:24])[CH:11]1[CH3:25])[CH:8]=[O:9]
Reactant: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(CO)cc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(C=O)cc1Br
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of 5-[2-bromo-4-(hydroxymethyl)phenyl]-2-[2-(trimethylsilyl)ethoxy]-methylisothiazolidin-3-one 1,1-dioxide (0.70 g, 1.6 mmol) in methylene chloride (15 mL) was added Dess-Martin periodinane (725 mg, 1.71 mmol) at room temperature. After stirring for 1 h, reaction solution was diluted with diethyl ether, quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with diethyl ether once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified with silica gel chromatography (5%–50% ethyl acetate/hexanes) to afford product as oil (0.69 g, 99%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.6 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.38 (m, 4H), 5.60 (dd, J=8.2, 6.2 Hz, 1H), 5.09 (dd, J=15.0, 11.3 Hz, 2H), 3.66 (dd, J=9.2, 7.4 Hz, 2H), 3.56 (dd, J=17.6, 8.2 Hz, 1H), 3.28 (dd, J=17.6, 6.2 Hz, 1H), 0.96 (dd, J=8.6, 7.0 Hz, 2H), 0.01 (s, 9H). LCMS found for C16H23BrNO5SSi (M+H)+: m/z=448, 450.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenylboronic acid to give (1-phenyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 287(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>CN(C=O)C>[CH:23]1([CH2:22][N:13]2[C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][S:16][C:12]2=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CCCCC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 0.10g, 0.3432 mmol) and bromomethylcyclohexane (1.00 mL) in DMF (1.00 mL) was added NaOH (approx. 0.13 g). The resulting mixture was stirred at 45° C. for 2 d during which it turned from deep red to bright orange. The reaction mixture was then cooled to room temp., filtered and concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2; 5% EtOAc/hex) to afford 1-(cyclohexylmethyl)-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (0.042 g, 32%) mp 85-7° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1>CC(N(C)C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:25]=2[CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-chloro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Br-:27].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(Cl)Cl>[Br:27][CH:17]1[CH2:16][CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:19][C:18]1=[O:20]
Reactant: [Br-]
Reactant: O=C1CCCCC(c2ccccc2)N1
Agent: C[N+](C)(C)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1NC(c2ccccc2)CCCC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 5.12 g (24.6 mmol) phosphorus pentachloride and 45 ml methylene chloride. To the stirring mixture cooled to 0° C. was added dropwise over 20 minutes, a solution of 4.65 g (24.6 mmol) 7-phenyl-hexahydroazepin-2-one and 3.98 ml (49.2 mmol) pyridine in 40 ml methylene chloride. To the stirring mixture at 0° C. was then added 9.25 g (24.6 mmol) phenyltrimethylammonium bromide tribromide. The reaction was then allowed to warm to room temperature and stirred for 3 hours. It was then evaporated, taken up in tetrahydrofuran, quenched with water, evaporated, and partitioned between water and methylene chloride. The organic layer was washed with water and saturated aqueous sodium bisulfite, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/hexane as eluent to afford the product as an oil, 4.0 g (61%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:36]=1>C(Cl)Cl.CN(C=O)C>[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:45][CH2:46][N:47]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:48][CH2:49]2)[N:36]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C#CC=C2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution 2-nitrobenzoic acid (42.6 mg, 0.25 mmol) in CH2Cl2 (2 mL) and DMF (0.5 mL) stirred at 0-5° C., was added 1-hydroxybenzotriazole (50 mg, 0.322 mmol) and, after 30′, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0.323 mmol). Afterwards, the Compound of Example 3 (53 mg, 0.25 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and kept overnight at the same temperature. After dilution with water and 1 N NaOH, the organic layer was separated and washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (CHCl3-1.4 N MeOH/NH3 100:0.1) yielded the title compound (82 mg).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][NH:29][CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
N4-Cyclohexyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (93 mg, 0.23 mmol) was dissolved in methanol (3 mL). Acetic acid (0.013 mL, 0.23 mmol) was added followed by formaldehyde (0.017 mL, 0.23 mmol) and sodium cyanoborohydride (14.48 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under reduced pressure. The crude material was dissolved in few drops of methanol, filtered and purified by preparative HPLC (acidic system) yielding N4-cyclohexyl-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (15.00 mg, 15.59%). MS (ES+) m/z 418.2 (M+H)+
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([O-:27])(=O)=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+]>CN(C)C=O>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([Cl:3])(=[O:27])=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of thionyl chloride (0.692 ml) and N,N-dimethylformamide (0.022 ml) was added sodium 6-octyloxy-2-naphthalenesulfonate (1 g) under ice-cooling. The mixture was stirred for 1.5 hours at 95° C., then evaporated under reduced pressure to give 6-octyloxy-2-naphthylsulfonyl chloride (1 g) .
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][N:15]=[C:16]=[O:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][NH:15][C:16]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][Cl:2])[N:5]=1)=[O:17]
Reactant: Nc1nc(CCl)cs1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of 4-(chloromethyl)thiazol-2-amine hydrochloride (7.55 g, 41 mmol) in DCM (150 mL) at 0° C. was added 3,4-dichlorobenzyl isocyanate (8.27 g, 41 mmol). A solution of DIPEA in DCM (30 mL) was added over a period of 30 minutes and the mixture was stirred overnight at room temperature. Evaporation of the volatiles followed by purification by column chromatography (EtOAc/heptanes 1/1) afforded 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea as an off-white solid (10.5 g, 30 mmol) in 73% yield. 1H NMR (DMSO-d6): δ 10.80 (bs, 1H); 7.60 (d, 1H); 7.55 (s, 1H); 7.11 (t, 1H); 7.05 (s, 1H); 4.63 (s, 2H); 4.30 (d, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.F[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]([C:16]([OH:18])=O)[CH2:10][CH2:9]2>C1(C)C=CC=CC=1.CN(C=O)C>[O:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]1[C:16]([Cl:3])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2cc(F)ccc2O1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCc2ccccc2O1
Temperature: 65 °C
Reaction time: 1.17 h
Yield: 124.8 %

Procedure:
Thionylchloride (109.21 g, 918 mmol) was added under nitrogen atmosphere at 20-25° C. to a suspension of 6-fluorochroman-2-carboxylic acid (90.00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Afterwards, the suspension was heated to an internal temperature of 60-70° C., whereupon a clear yellow solution was obtained under simultaneous evolution of a gas. The reaction was completed within 70 min at this temperature, and the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar) to yield the chroman-2-carboxylic acid chloride as a yellow oil (112.65 g). The crude product was dissolved in methylene chloride (65 ml) and added slowly under nitrogen atmosphere to a solution of Meldrum's acid (70.90 g, 482 mmol) and pyridine (72.62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0-10° C. The reaction mixture was allowed to warm to 20-25° C. within 50 min. and stirred at this temperature for additional 30 min. Methylene chloride (325 ml) and water (325 ml) were then added to the formed brown suspension. The two phase mixture was stirred for 5 min, separated, and the organic layer was subsequently extracted twice with water (200 ml each), then with 2N aqueous HCl solution (250 ml) and finally with water (250 ml). After drying over Na2SO4, the organic layer was filtrated and concentrated in vacuo (≦50 mbar) to give a brown, viscous oil (170.76 g), which crystallized after 10 min at room temperature. The solid was slurried at 20-25° C. in diisopropyl ether (500 ml) for 2 h. After filtration of the suspension, the wet product was washed with diisopropyl ether (70 ml) and dried in vacuo (13 h at 40° C.) to give a yellow-ocher colored solid (yield: 114.71 g, HPLC-purity: 96.98%).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][OH:23].N1C=CC=CC=1.Cl>C(Cl)CCl>[CH2:26]([O:25][C:21](=[O:24])[CH2:22][O:23][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:27]
Reactant: CCOC(=O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Trityl chloride (279 g, 1.0 mol) was dissolved in EDC (680 ml, 5 ml/g with respect to ethyl glycolate), and ethyl glycolate (135 g, 1.3 mol) was added to the mixture. Pyridine (99 g, 1.25 mol) was added thereto, and the mixture was stirred for 19 hours at 40° C. After completion of the reaction was confirmed by HPLC, 0.5 N aqueous hydrochloric acid solution (270 ml, 2 ml/g with respect to ethyl glycolate) was added to make the reaction solution a two-phase solution, which was then extracted. After the extraction was performed once again, EDC was distilled under reduced pressure. In order to obtain the compound of formula (8) as a solid form, hexane (680 ml) was added to the concentrated compound, the temperature was lowered to 0° C., and the mixture was stirred for about 3 hours and filtered.