Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(#N)C>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:17](=[O:19])[CH3:18])[C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)N1CCCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.874 g, 0.00397 mol), acetic anhydride (8.418 mL) and acetonitrile (10 mL) were combined in a round bottom flask. The mixture was stirred at room temp for 17 hours and then heated at 60° C. for 2 days. The mixture was concentrated under reduced pressure, then purified by normal phase chromatography eluting with 10% to 50% ethyl acetate in hexane to yield a yellow oil, 1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (1.04 g, 61%). LCMS: m/z=263.25 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.15 (m, 1H), 7.98 (m, 1H), 7.65 (d, 1H, J=8.6 Hz), 4.82 (m, 1H), 2.60 (m, 1H), 2.24 (m, 1H), 1.95 (s, 3H), 1.81 (m, 1H), 1.70 (m, 1H), 1.56 (m, 6H), 1.28 (m, 1H).
Reaction SMILES: [O:1]=[S@@:2]1[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3]1.[CH2:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[S@@:2]1[C@H:7]2[N:6]([C:9](=[O:10])[C@H:8]2[NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:22])=[C:4]2[C@@H:3]1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41]2
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C2=C3CC(c4ccccc4)[C@@H]3[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a suspension of p-methoxybenzyl (1S,6R,7R)-1-oxo-7-phenylacetamido-3-trifluoromethanesulphonyloxyceph-3-em-4-carboxylate (30 mg, 0.05 mmol) and styrene (300 μl, 2.62 mmol) in dichloromethane (3 ml), was added diisopropyl-ethylamine (10 μl, 0.057 mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compounds (14.7 mg, 53%), νmax (CH2Cl2), 1790, 1728, 1689 cm-1 ; δH (CDCl3) 7.41-7.16 (12H, m) 6.89 (2H, m) 6.67 (0.4H, d, J 9.7 Hz), 6.52 (0.6H, d, J 9.8 Hz), 5.98 (0.4H, dd, J 9.7, 4.9 Hz), 5.86 (0.6H, dd, J 9.8, 4.9 Hz), 5.28 (ABq, J 11.9 Hz), 5.23 (0.8H, ABq, J 11.8 Hz), 4.38 (1H, m), 4.31 (0.6H, m), 4.0 (1.4H, m), 3.80 (3H, s), 3.73-3.82 (4H, m).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:16]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O-])=[O:41])[N:35]=[CH:34]2)(=O)C.[NH4+].[OH-:44]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:16]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:44][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:41])[N:35]=[CH:34]2
Reactant: [OH-]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2c1
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)c5cccnc5)c4)nc4ccc(O)cc34)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A mixture of 5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.374 g, 0.607 mmol) and 28% NH4OH (0.45 mL) in MeOH (50 mL) was stirred at RT for 24 h. The volatiles were removed in vacuo and the residue was washed with Et2O to give the product tert-butyl 5-(6-hydroxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.318 g, 0.554 mmol, 91%).
Reaction SMILES: [O:1]=[C:2]1[CH:12]=[N:11][C:10]2=[C:13]3[N:3]1[CH2:4][C@@H:5]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)[N:6]3[C:7](=[O:14])[CH:8]=[CH:9]2.[ClH:30]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:5]2[N:6]3[C:13]4[N:3]([C:2](=[O:1])[CH:12]=[N:11][C:10]=4[CH:9]=[CH:8][C:7]3=[O:14])[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(1R)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl}-4-piperidinyl)carbamate (76 mg, 0.189 mmol) in chloroform (2 ml) at room temperature was treated with 4M HCl in 1,4-dioxane (2 ml). A solid precipitated out and the mixture was stirred room temperature. After 0.5 h the reaction was complete so some methanol was added to dissolve most of the solid, followed by toluene and all the solvents were removed to afford the product as a dark yellow solid (70.9 mg, 99%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[N:19]=[CH:18][C:17]4[N:23]([CH3:34])[C:24](=[O:33])[N:25]([C:26]5[C:27]([CH3:32])=[N:28][N:29]([CH3:31])[CH:30]=5)[C:16]=4[C:15]=3[CH:14]=2)[CH:12]=1)([CH3:6])[CH3:5].CO.[BH4-].[Na+]>C1COCC1>[CH3:31][N:29]1[CH:30]=[C:26]([N:25]2[C:16]3[C:15]4[CH:14]=[C:13]([C:11]5[CH:10]=[N:9][CH:8]=[C:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH:12]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:23]([CH3:34])[C:24]2=[O:33])[C:27]([CH3:32])=[N:28]1
Reactant: COC(=O)C(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)CO)c4)cc3c21

Procedure:
To a solution of 2-{5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionic acid methyl ester (Stage 229.1.1, 0.134 mmol) in THF (1.2 ml) were added MeOH (0.009 ml) and NaBH4 (0.185 mmol) four times during the course of the heating at 40° C. for 39 h. After that, the RM was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white foam. (HPLC: tR 2.06 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.62-8.58 (m, 2H), 8.15-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.74-7.71 (m, 1H), 7.62-7.59 (m, 1H), 4.79 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.50 (d, 2H), 1.96 (s, 3H), 1.30 (s, 6H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH2:27][CH3:28])[C:10]2=[O:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH2:27][CH3:28])[C:10](=[O:29])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:31]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of Example 50 (100 mg, 0.23 mmol) and 3-(chlorosulfonyl) benzoic acid (57 mg, 0.26 mmol) in THF (5 ml) was added DIEA (45 μl, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours then concentrated under vacuum. The residue was partitioned between EtOAc and water. The pH was adjusted to pH=2. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The obtained solid was chromatofraphed over silica gel using DCM/MeOH (80/20) to yield the above-titled compound (63 mg), mp=145° C. 1H NMR (CDCl3): 8.63 (1H, s), 8.41 (1H, d, J=7.5 Hz), 8.17 (1H, d, J=7.4 Hz), 7.77 (1H, t, J=7.7 Hz), 7.62 (2H, d, J=7.7 Hz), 7.18–7.26 (3H, m), 6.60 (2H, s), 3.4–4.2 (7H, m), 1.45 (3H, t, J=6.8 Hz).
Reaction SMILES: [N:1]1([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36](O)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36]([NH:16][CH:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NC(CC1CCCO1)c1ccccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCO2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from 2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>ClCCl>[CH3:32][O:31][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Solvent: ClCCl
Product: CCn1cnc2c(Nc3ccc(NC(=O)OC)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
trans 4-[6-(4-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (example 77, stage 1.2, 100 mg, 0.272 mmol) is suspended in 1 ml dichloromethane and treated with 21 μl (0.272 mmol) methyl chloroformate. The reaction mixture is stirred at RT for 20 h after which another equivalent of methyl chloroformate (21 μl, 0.272 mmol) is added. After additional 23 h at RT the reaction mixture is evaporated and the product purified by chromatography on silica gel (CH2Cl2/MeOH 95:5). {4-[9-ethyl-2-(trans-4-hydroxy-cyclo-hexylamino)-9H-purin-6-yl-amino]-phenyl}-carbamic acid methyl ester is obtained as tan crystals, 93 mg (81%). m.p. 131-135° C.; MS [M+H]+426; HPLC (System h) tR=4.84 min.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][C@@H:30]1[CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:9][C:10]([F:11])([F:13])[F:12])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])([O-:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NC[C@@H]2CCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (78 mg, 0.224 mmol) and S-(+)-tetrahydrofurfurylamine (0.025 mL, 0.246 mmol) in 3 mL of EtOH containing Et3N (0.047 mL, 0.336 mmol). The product was purified by flash chromatography on silica gel using 1:1/hexanes:EtOAc as eluent. Yield: 95 mg (95%); 1H NMR (CDCl3) 1.72 (m, 1H), 1.99 (m, 2H), 2.13 (m, 1H), 3.99 (m, 1H), 3.53 (m, 1H), 3.85 (m, 1H), 3.97 (m, 1H), 4.25 (m, 5H), 6.99 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.51 (brs, 1H); MS (ESI) 430.28 (MH+).
Reaction SMILES: Cl[CH:2]([Cl:23])[B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:8])[C:5]([CH3:22])([CH3:21])[O:4]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1.C(OCC)(=O)C>[Cl:23][CH:2]([B:3]1[O:7][C:6]([CH2:9][CH2:10][CH:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])([CH3:8])[C:5]([CH3:21])([CH3:22])[O:4]1)[CH2:24][CH3:25]
Reactant: CC[Mg]Br
Reactant: CC(CCC1(C)OB(C(Cl)Cl)OC1(C)C)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
0.86 g (2.3 mmol) of tert-butyl 5-[2-(dichloromethyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to -78° C. under a nitrogen atmosphere. 2.6 ml (2.6 mmol) of 1 M ethylmagnesium bromide in tetrahydrofuran were added dropwise, the resulting solution wasstirred for 16 hours while slowly warming to room temperature and then diluted with ethyl acetate and extracted with 2M hydrochloric acid and brine. The organic phase was dried over sodium sulphate and then evporatedunder a vacuum to give 0.83 g of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[CH3:23])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[CH3:23])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Agent: [Na+]
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
A mixture of 0.7 g (1.9 mmol) of 7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile and 0.62 g (9.5 mmol) of sodium azide is heated at 60° C. under nitrogen for 24 hours. The mixture is cooled and poured onto ice. The solid is collected by filtration, washed with water and dried to yield 0.65 g of 7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile as a yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C@:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([OH:17])[C@@H:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)[CH3:10])(=O)C.O>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@@:8]([OH:17])([C@@H:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)[CH3:10])[CH2:7][OH:6]
Reactant: CC(=O)OC[C@@](O)(c1ccc(F)cc1F)[C@H](C)c1ccncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](c1ccncn1)[C@@](O)(CO)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
2N Sodium hydroxide solution (40 ml) was added with stirring over 0.25 hour to a solution of the product of part (ii) (23.3 g) in methanol (80 ml) and stirring was continued for a further 0.25 hour. Water (150 ml) was added and the mixture was cooled. The solid was filtered off, washed with water and dried to give the title compounds, (17.4 g), m.p. 148.5°-150.5°.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccco1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccco1
Temperature: 100 °C
Reaction time: 9 h
Yield: 97 %

Procedure:
A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After cooling as it was, the reaction solution was concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([N:13]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21](=[O:32])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH2:15][CH2:14]1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:33])[CH:4]([N:13]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21](=[O:32])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH2:15][CH2:14]1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(CC(=O)O)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 8 h

Procedure:
A solution of 0.30 g (0.60 mmol) of) 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-succinic acid 4-tert-butyl ester 1-methyl ester in 1.2 ml of dioxane was cooled down to ˜6° C. and 1.50 ml (6.01 mmol) of hydrochloric acid 4M in dioxane, then 1 drop of water were added and stirring was continued overnight at RT. The solution was evaporated, dissolved in acetonitrile and evaporated (2×) to give the titled compound in quant. yield as yellow oil. MS: 441.2 (M−H−, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][S:5](=[O:18])[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1nsnc1OC
Solvent: ClC(Cl)Cl
Product: COC1=NS(=O)N=C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole (35.2 g; 24.1 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2749 (1975)] in 100 ml of chloroform was added over a period of 3 minutes to a stirred solution of m-chloroperbenzoic acid (50.7 g; 25.0 mmoles; 85% assay) in 900 ml of chloroform at 20°, using a cooling bath to keep the exothermic reaction from rising above 32°. After stirring for 3 hours at ambient temperature, the excess peracid was reacted with an additional 2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole and stirred for 1 hours.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=1.IC>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:1](=[O:4])[N:12]([CH3:11])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Reaction time: 18 h

Procedure:
Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3-nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in N,N-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (MI).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[OH:19])[CH:14]=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH:27]([CH3:29])[CH3:28])[CH:14]=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Yield: 86 %

Procedure:
To a stirred suspension of 3-(1-admantyl)-4-hydroxybenzaldehyde (0.5 g, 1.95 mmol) and K2CO3 (0.276 g, 2 mmol) in anhydrous DMF (5 ml) was added 2-bromopropane (1 ml) and the mixture was reflux for 2 h. The reaction mixture was brought to room temperature and diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.25 g, 86%), as a colourless solid. 1H-NMR (CDCl3) 1.42 (d, 6H, J=6 Hz); 1.76 (broad s, 6H); 2.07 (broad s, 3H); 2.12 (s, 6H); 4.69-4.78 (m, 1H); 6.91 (d, 1H, J=8.44 Hz); 7.66 (dd, 1H, J=2.13, 8.45 Hz); 7.76 (d, 1H, J=2.11 Hz); 9.84 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 411.00 g/mol.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
Resorcinol monoacetate (6.10 g, 40 mmol) in DMF (10 mL) was added dropwise to the mixture of NaH (95%, 0.92 g, 40 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 10 min. Benzyl bromide (6.85 g, 40 mmol) in DMF (10 mL) was then added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched slowly with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a white solid (5.30 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 2.28 (s, 3 H), 5.03 (s, 2 H), 6.72 (m, 2 H), 6.85 (dd, 1 H, J=1.2, 4.1 Hz), 7.27 (t, 1 H, J=7.9 Hz), and 7.41 (m, 5 H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([F:16])[C:13](F)=[C:12]([F:18])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([OH:23])[C:21]#[CH:22].[H-].[Na+]>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9](=[O:19])[C:10]2[CH:11]=[C:12]([F:18])[C:13]([O:23][CH2:20][C:21]#[CH:22])=[C:14]([F:16])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C#CCO
Reactant: O=C(NCC1CCCCC1)c1cc(F)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1c(F)cc(C(=O)NCC2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 10 ml of DMF were added 0.50 g of N-cyclohexylmethyl-3,4,5-trifluorobenzamide and 0.15 g of propargyl alcohol and to the mixture obtained was added 100 mg of sodium hydride at 0° C. The mixture obtained was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.49 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-difluorobenzamide (hereinafter, described as the compound 32 of the present invention) represented by the formula: