Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:2]=2)[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:28][CH2:27]1)[CH3:24]
Reactant: CCOC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-ethoxypiperidine (0.101 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.175 g, 62.6% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.20-1.93 (4H, m), 2.98-3.27 (2H, m), 3.33-3.41 (1H, m), 3.42-3.54 (3H, m), 3.93 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.31 (1H, s), 7.33-7.42 (2H, m), 7.79-7.90 (2H, m), 7.95 (1H, m), 8.26 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.81 min (M+H=392.13).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(S(=O)(=O)c3ccc(O)cc3)C2)CC1

Procedure:
The title compound, MS: m/e=411.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure described for example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33](Cl)[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:37]([OH:42])(=[O:41])[CH2:38][CH2:39][CH3:40].C(N(C(C)C)C(C)C)C>C(OCC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33]([O:41][C:37](=[O:42])[CH2:38][CH2:39][CH3:40])[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CC(Cl)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Reactant: CCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCC(=O)OC(C)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21

Procedure:
1-chloroethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2.0 g, 3.60 mmol) was stirred with butyric acid (1.0 mL, 10.81 mmol) and ethyldiisopropylamine (0.94 mL, 5.41 mmol) at 50° C. for 48 hours. The reaction was diluted with diethyl ether (20 mL) and quenched with aqueous saturated NaHCO3 (40 mL). The reaction was extracted with ethyl acetate (2×50 mL) and the combined organics were washed with water (50 mL), brine (50 mL) then dried (MgSO4). The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give 1-(butyryloxy)ethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-90 (628 mg, 23% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine (1.00 g; 3.76 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.37 g; 4.51 mmol), N,N-diisopropylethylamine (1.55 g; 12.0 mmol) and PyBOP (2.34 g; 4.51 mmol) are added sequentially. The reaction is stirred for 2.5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (84) as a solid. ESMS:MH+ 516.2
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:28].[Na+].[Na+]>S(=O)(=O)(O)O>[C:13]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])[C:25]([NH2:26])=[O:28])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(CCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenylpropane (11.1 g-see Preparation 5) in 90% sulphuric acid (66 ml) was heated at 100° for 1 hour. The mixture was allowed to cool to room temperature and poured into ice/water (300 ml). The aqueous mixture was basified with saturated aqueous sodium carbonate and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound, yield 10.6 g. A sample recrystallised from ethanol had a melting point of 145°-148°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: [H][H]
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(N)c(=O)[nH]c1C

Procedure:
A yellow solution of the 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone (10 g, 55 mmol) in a mixture of methanol and tetrahydrofuran (100 mL, 1:1 v/v) was reduced catalytically in the presence of 7% palladium on charcoal (0.7 g) under and atmosphere of hydrogen (50 psi) at room temperature over a period of 3.5 hours. The resultant mixture was filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure (15 torr) to provide the corresponding aminopyridone.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
N2-(tert-Butoxycarbonyl)-L-alanine (1.13 g, 5.83 mmol) is dissolved in dry DCM (6 ml), some 3 Å molecular sieves are added, and the mixture is then cooled to 0° C. Benzyl alcohol (1.81 ml, 17.48 mmol, 3 equivalents), EDCI (2.23 g, 11.65 mmol, 2 equivalents), and DMAP (71 mg, 0.58 mmol, 0.1 equivalent) are added. The mixture is stirred for 150 min, during which it is allowed to slowly warm to RT. The mixture is then concentrated to dryness and the residue is worked up by chromatography (Biotage, cyclohexane-ethyl acetate 9:1). Product-containing fractions are combined and concentrated. The title compound is obtained in a yield of 1.03 g (63% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Yield: 106.6 %

Procedure:
A mixture of 350 g of the product of Step A, 35 g of p-toluene sulfonic acid and 3.5 liters of toluene was refluxed for 45 minutes and was then cooled, washed with water, dried and evaporated to dryness under reduced pressure to obtain 328 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[C:31]1[O:32][C:33]2[C:38]([N:39]=1)=[CH:37][CH:36]=[CH:35][N:34]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:59]1([CH2:64][CH2:65][CH2:66]O)[CH2:63][CH2:62][CH2:61][CH2:60]1>ClCCl.CN(C=O)C>[N:39]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[O:32][C:31]=1[C:19]1[C:18]([NH2:17])=[N:23][CH:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:66][CH2:65][CH2:64][N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)=[CH:26][CH:25]=2)[CH:20]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)cc1-c1nc2cccnc2o1
Reactant: OCCCN1CCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ncc(-c2ccc(OCCCN3CCCC3)cc2)cc1-c1nc2cccnc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (DTAD) (227 mg) in dichloromethane (1 ml) was added to a stirred solution of 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)phenol (100 mg), polystyrene bound triphenylphosphine (330 mg, 3 mmol/g) and 3-pyrrolidin-1-ylpropan-1-ol (64 mg) in DMF (2 ml) at room temperature under argon. The resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered and the resulting solid was washed with methanol. The filtrates were combined, concentrated to dryness and diluted with DCM/TFA (1 ml: 1 ml). The mixture was stirred for 30 min and concentrated. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 1% acetic acid) and Methanol as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-oxazolo[5,4-b]pyridin-2-yl-5-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]pyridin-2-amine (36 mg) as a solid. NMR Spectrum: (DMSOd6) 1.86 (bs, 4H), 2.03-2.15 (m, 2H), 3.02-3.33 (m partially hidden by H2O, 6H), 4.11 (t, 2H), 7.06 (d, 2H), 7.53 (dd, 1H), 7.68 (d, 2H), 7.77 (bs, 2H), 8.30 (dd, 1H), 8.40 (dd, 1H), 8.46 (d, 1H), 8.58 (d, 1H); Mass spectrum: M+H+ 416. The 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)phenol used as starting material was made as follows:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:38])(=[O:37])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[CH:31]=[CH:30]3)[S:24]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])(=[O:37])=[O:38])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(C)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 11).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:32](=[O:33])[CH2:31][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CC1CCOCC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CC4CCOCC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and tetrahydropyran-4-yl-acetic acid; MS: m/e=446.1 (M+H+).
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1
Reactant: C[C@@H]1C[C@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl ((1S,2R,3R,5S)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate in 98% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.71 min.
Reaction SMILES: [CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)=[O:4]>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]=1)=[O:4]
Reactant: CN(C(=O)CCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)CCCCSc1nc2ccccc2n1CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
tert-Butyl {2-[4-(methyl-phenyl-carbamoyl)-butylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor F-01b, 25.6 mg, 0.06 mmol) is dissolved in TFA/dichloromethane (1:1, 3 ml) and stirred for 3 h at rt. Evaporation of the solvent in vacuo and drying under high vacuum yields the title compound (19.4 mg) in 87% as a yellow oil: tR=5.20 min (LC-1), ESI-MS (pos.): m/z 398.20 [M+H]+, ESI-MS (neg.): m/z 396.19 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.56 (m, 4H, CH2CH2), 2.05 (m, 2H, CH2C═O), 3.14 (s, 3H, NMe), 3.22 (m, 2H, SCH2), 5.00 (s, 2H, CH2CO2), 7.18-7.32 (m, 5Harom), 7.38 (m, 2Harom), 7.53 (m, 2Harom).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:17])=[CH:14][CH:15]=O.C(O)(=O)CC>>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][CH2:3]/[C:2](/[CH3:1])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[O:11]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: CCC(=O)O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Yield: 84 %

Procedure:
100 parts of geraniol, 30 parts of 3,3-dimethylacrolein and 2.5 parts of propionic acid are heated together at refluxing temperature for four hours while stirring. The product is distilled. 83.5 parts of farnesal is obtained having a boiling pointof 120° to 123° C at 0.2 mm. The yield is 84% of theory at a conversion of 63% (based on 3,3-dimethylacrolein).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:13]2[CH3:12])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2c(C)nc3ccccc32)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (10.3 g), 2-methylbenzimidazole (8.7 g) and sodium carbonate (7.5 g) was heated with stirring in dimethylformamide (40 cm3) at 130° for 16 hours under nitrogen. The cooled mixture was evaporated in vacuo, water (50 cm3) added and the mixture extracted with methanol:chloroform, 1:10 by volume. The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of appropriate fractions afforded a solid which was recrystallised from hexane/acetone to give the title compound, m.p. 144°-6°, (10.65 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])[CH2:8]1.[CH3:28][NH2:29]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([NH:29][CH3:28])=[O:23])=[O:16])[CH2:8]1
Reactant: O=C(O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 0.67 h

Procedure:
N,N′-carbonyldiimidazole (0.0132 g) was added to a stirred solution of Intermediate 26 (0.030 g) in N,N-dimethylformamide (2 ml), and the mixture stirred at 22° C. under nitrogen for 40 min. Methylamine (2.0M solution in tetrahydrofuran, 0.102 ml) was added, and stirring was continued at 22° C. for 17 h. The mixture was applied directly to a sulphonic acid ion exchange cartridge (2 g Isolute SCX), and eluted with methanol followed by 10% 0.880 ammonia in methanol to give a gum (0.042 g). Purification by chromatography on silica gel (1 g Varian Bond Elut cartridge), eluting with chloroform, ether, ethyl acetate, acetone, and methanol, gave a gum (0.025 g), which was further purified by mass directed preparative HPLC to give the title compound as a colourless gum (7.2 mg).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([C:24]([F:27])([F:26])[F:25])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34]>CN1CCCC1=O>[CH:29]1([CH2:28][N:3]2[C:2]([N:39]3[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([C:24]([F:26])([F:27])[F:25])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:31][CH2:30]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)c(C(F)(F)F)n1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4C(F)(F)F)nc3n2CC2CC2)CC1
Temperature: 150 °C
Reaction time: 7 h
Yield: 48.3 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.16 mmol) and N-methanesulfonylpiperazine (135 mg, 0.8 mmol) and the resulting mixture was stirred at 150° C. for 7 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column; NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (45 mg, 47%) as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[CH:1]1([CH:7]([CH3:11])[C:8]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][C:26]([C:24]4[CH:25]=[C:20]([N:17]5[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]5)[N:21]=[C:22]([NH2:36])[N:23]=4)=[CH:27][CH:28]=3)[CH2:33]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C(=O)O)C1CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)C1CCCCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 2-cyclohexylpropanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=463.3.