Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCCCCCC)[C@H]2[OH:42])=C(N)N=1.CS(C)=O.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: CCCCCCCCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-diamino-9-(2'-O-nonyl-β-D-ribofuranosyl)purine and 2,6-diamino-9-(3'-O-nonyl-β-D-ribofuranosyl)purine (≈80:20 mixture, 29 g) in 0.1 M sodium phosphate buffer (50 ml, pH 7.4), 0.1 M tris buffer (1800 ml, pH 7.4) and DMSO (1080 ml) was treated with adenosine deaminase (1.6 g) as per the procedure of Example 3 to yield 60 g of product as an oil. An analytical product was purified by silica gel chromatography and recrystallized from EtOAc. m.p. 258-259° C. 1H NMR (DMSO-d6) δ 0.96 (t, 3, CH3, J=7 Hz); 1.17 [m, 12, O--CH2 --CH2 --(CH2)6 ]; 1.42 [m, 2, O--CH2CH2 (CH2)6 ]; 3.27-3.61 (m, 4, H-5', O--CH2 (CH2)7 ]; 3.95 (m, 1, H-4'), 4.10-4.13 (m, 2, H-2', H-3'); 5.13-6.06 (m, 2, 3'-OH 5'-OH); 5.80 (d, 1, H-1', J=6.4 Hz); 6.47 (s, 2, 2-NH2); 7.98 (s, 1, 8-H) and 10.64 (s, 1, N1 amide). Anal. Calcd. for C19H31N5O5 : C, 55.73; H, 7.63; N, 17.10. Found: C, 55.67; H, 7.66; N, 17.02.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (253 mg, 1.02 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (335 mg, 1.00 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (574 mg, 1.23 mmol) in chloroform (10 mL). DIEA (930 μL, 5.32 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (132 mg, 0.25 mmol, 24%): LC-MS (ES) m/z=517 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(CC2CCOCC2)c2nc(Br)cnc2N1
Temperature: 40 °C
Yield: 78.6 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (8.0 g, 19.01 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.63 g, 22.81 mmol) and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mL round bottom flask, suspended in acetonitrile (80.0 mL) and heated to 40° C. for 16 h. The resulting white precipitate was filtered, washed with acetonitrile followed by hexanes and dried under vacuum to afford the title compound (4.89 g, 14.95 mmol, 79% yield). MS (ESI) m/z 327.4 [M]+, 329.5 [M+2]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([N:10]1[C:14]([CH3:15])=[C:13]([C:16](=O)[CH3:17])[CH:12]=[N:11]1)(C)(C)C.[ClH:19].NO.[OH-].[Na+].C[N:25]([CH3:28])C=O>>[Cl:19]/[C:16](/[C:13]1[CH:12]=[N:11][NH:10][C:14]=1[CH3:15])=[CH:17]\[C:28]#[N:25]
Reactant: CC(=O)c1cnn(C(C)(C)C)c1C
Reactant: Cl
Reactant: CN(C)C=O
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]ncc1/C(Cl)=C/C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
To N,N-dimethylformamide (12.1 g) was added phosphorus oxychloride (25.4 g) by small portions under ice-cooling, and the mixture was stirred at room temperature for 15 min. Thereto was added 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)ethanone (7.47 g) produced above by small portions under ice-cooling, and the reaction mixture was stirred at 50° C. for 30 min. Thereto was added a powder (11.5 g) of hydroxylamine hydrochloride by small portions at 50° C., and the reaction mixture was stirred at 50° C. for 30 min. Ice water (200 mL) was added to the reaction mixture, and the mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from diethylether to give the title compound (3.02 g) as a pale-yellow powder.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].CC[O-].[Na+].[CH2:10]([CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16])[CH2:11][CH2:12][CH3:13]>CCO>[CH2:10]([C:14]1[C:15](=[O:16])[NH:2][C:3](=[S:4])[NH:5][C:20]=1[CH3:22])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C(C)=O)C(=O)OCC
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCc1c(C)[nH]c(=S)[nH]c1=O
Temperature: 25 °C

Procedure:
Sodium metal (1.85 g, 80.5 mmol) is dissolved in EtOH (50 mL). Next, thiourea (5.11 g, 67.1 mmol) is added to the NaOEt solution, followed by ethyl 2-n-butylacetoacetate (2.5 g, 13.4 mmol). The reaction mixture is stirred at reflux for 3 hours and then allowed to cool to room temperature overnight. The EtOH is removed in vacuo. The residue is then suspended in H2O (50 mL) and the resulting mixture carefully treated with concentrated HCl (˜7.5 mL) just until pH 4 is reached. After stirring for 15 minutes, the suspension is filtered, and the solid thoroughly washed with H2O. Drying affords pure 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a slightly off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.28 (br s, 1H), 12.05 (br s, 1H), 2.21 (m, 2H), 2.18 (s, 3H), 1.30–1.21 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 199 [M+1].
Reaction SMILES: [CH:1](/[C@@H:5]1[C@@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11])=[CH:2]\[CH:3]=[CH2:4].CN1C=CN=C1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[F:30][C:31]1[C:38]([F:39])=[CH:37][C:36]([F:40])=[C:35]([F:41])[C:32]=1[CH2:33]O>CC#N>[CH:1](/[C@@H:5]1[C@@H:7]([C:8]([O:10][CH2:33][C:32]2[C:35]([F:41])=[C:36]([F:40])[CH:37]=[C:38]([F:39])[C:31]=2[F:30])=[O:9])[C:6]1([CH3:12])[CH3:11])=[CH:2]\[CH:3]=[CH2:4]
Reactant: C=C/C=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1c(F)c(F)cc(F)c1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: CC#N
Product: C=C/C=C/[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)cc(F)c2F)C1(C)C
Yield: 97.6 %

Procedure:
In a similar way to that described in example 1 part b., 2.38 g (14.3 mmol) of (1R,3R)-3-((E)-buta-1,3-dienyl)-2,2-dimethylcyclopropane-1-carboxylic acid are added with 3.4 ml (43 mmol) of N-methyl imidazole dissolved in 43 ml of CH3CN, and reacted with 3.26 g (17.2 mmol) of tosyl chloride dissolved in 19 ml of CH3CN then with 2.6 ml (14.3 mmol) of 2,3,5,6-tetrafluorobenzyl alcohol dissolved in 16 ml of CH3CN. After purification on silica gel column with 100/1 (v/v) petroleum ether/ethyl ether as eluent, 4.58 g of an oily product with an E/Z ratio of 97/3 and a purity equal to 96.1% are obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:34])=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccc2-c2cccc(O[Si](C)(C)C(C)(C)C)c2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2N2CC[C@H](N)C2=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-1-[3′-(tert-butyldimethylsilyloxy) biphen-2-yl]-2-oxopyrrolidine, as described above in Step E, (888 mg, 1.84 mmol) was dissolved in CH2Cl2 (20 mL), cooled to 0° C., and trifluoroacetic acid (4 mL) was added. After 3 hours, the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1.O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)COc1cccc2ccccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
In a nitrogen atmosphere, a suspension of 34 g of 1-naphthol, 40 g of 2,2,2-trifluoroethyl p-toluenesulfonate, 33 g of potassium carbonate, and 80 g of dimethyl sulfoxide was heated and stirred at 100° C. for 12 hours. After cooling, 100 g of water and 200 g of toluene were added to the suspension, after which an organic layer was taken out. It was washed 5 times with 100 g of 5 wt % sodium hydroxide aqueous solution, then 4 times with 100 g of water. The organic layer was concentrated, obtaining 36 g of oily matter. It was distilled in vacuum (75° C./13 Pa), obtaining 28 g (yield 76%) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([F:27])[CH:14]=3)[C:5]2=[N:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([F:27])[CH:14]=3)[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Reactant: CNC
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)OC(C)(C)C)c(F)c3)ccnc2n1

Procedure:
Method D6 was used with tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate (270 mg, 0.67 mmol) and dimethylamine to give the product as a yellow solid. Yield: 233 mg (91%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]2[CH:12]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)CO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]4[CH:12]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc2nc(CCl)cn2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(CN3CCN(c4ccc(F)cc4)CC3)cn2c1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 55.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine (0.302 g), 1-(4-fluorophenyl) piperazine (Aldrich; 0.319 g), triethylamine (Aldrich; 0.26 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. The cooled mixture is then poured into saturated aq. sodium bicarbonate and extracted several times with dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane/ammonium hydroxide (4/96/0.25) and crystallized from ethyl acetate/hexane to give 0.300 g of the title compound; mp 112-112.5° C.; ms m/z 324; IR (mineral oil) 1511, 804, 1234, 1246, 1345 cm-1 ; 1H NMR (CDCl3) δ2.31, 2.74, 3.15, 3.76, 6.90, 7.46, 7.86.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH:27]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.95 g, 1.80 mmol) (prepared in the previous step) in 10 mL of DCM was added 0.4 mL of EtOH and 10 mL of TFA and the mixture stirred for 1 h at RT. The mixture was concentrated and triturated with Et2O to give 0.68 g (95%) of a white solid: 1H-NMR (400 MHz, CDCl3): δ 11.23 (br s, 1H), 9.52 (br s, 1H), 8.27 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.41 (dd, J=2.3, 8.7 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 5.82 (m, 1H), 2.28 (m, 2H), 2.10 (m, 2H), 1.58 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C19H19BrN4O, 399.1 (M+H). found 399.0.
Reaction SMILES: C(Cl)([Cl:3])=O.O1CCCC1.[CH3:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=S>CN(C)C=O>[ClH:3].[CH3:10][NH:11][C:12]([Cl:3])=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cl
Reactant: CNC(=S)Nc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(Cl)=Nc1ccccc1
Product: Cl
Reaction time: 0.5 h

Procedure:
After passing 6.3 g of phosgene into 40 ml of absolute tetrahydrofuran at room temperature, 8 g of 1-methyl-3-phenylthiourea are added, with stirring, the color of the suspension changing instantaneously to yellow. After adding 0.5 ml of dimethylformamide, the mixture is stirred for 20 hours at room temperature, nitrogen is then passed through the reaction mixture for about 30 minutes, in order to drive off the phosgene, and the crystals are filtered off and washed with tetrahydrofuran. Crystals with a melting point of 169° C. (with decomposition).
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:13]3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].[CH3:25]I.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:25][C:11]1([CH3:2])[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, Step A) (360 mg, 1.2 mmol) in DMF (20 mL) at rt was added NaH (172 mg, 4.8 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 6 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,1,3-trimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (370 mg, 90%) as an oil. MS [M+H]+342. 1H NMR (CDCl3, 300 MHz): δ 7.12 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.69 (s, 2H), 4.23 (m, 2H), 3.86 (m, 2H), 3.43 (s, 3H), 3.01 (m, 2H), 1.81 (s, 6H), 1.24 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[CH:10]=[C:9]([C@H:11]([NH:24]S(C(C)(C)C)=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=2)[N:8]=[N:7]1)[CH3:2].[ClH:32].CCOCC>CCO>[Cl-:32].[Cl-:32].[NH3+:24][C@@H:11]([C:9]1[N:8]=[N:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])[CH:10]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][NH+:13]=1
Reactant: Cl
Reactant: CCOC(=O)Cn1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)Cn1cc([C@H]([NH3+])c2ccc(OCC(F)(F)F)c[nH+]2)nn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of ethyl(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)acetate (0.285 mg, 0.615 mmol) in 5.0 ml of EtOH was added 2.0N HCl in Et2O (3.070 ml, 6.150 mmol), and the mixture was stirred at RT for 30 min. Solvent removed and the residue was dried under vacuum to give the crude title compound (0.260 g, 99%). ES-MS [M+1]+: 360.1. This intermediate was carried over to the next step without further purification and characterization.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.COCCOC.[C:16]([C:20]1[C:21]([Cl:29])=[C:22]([C:26](Cl)=[O:27])[N:23]([CH3:25])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].[NH4+].[Cl-].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CCOC(C)=O.O>[Br:8][C:6]1[N:7]=[C:2]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:3]([NH:9][C:26]([C:22]2[N:23]([CH3:25])[N:24]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:21]=2[Cl:29])=[O:27])=[N:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2nc(Br)cnc2NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dibromo-pyrazin-2-ylamine (252 mg, 1.00 mmol) in DME (10 mL) 60% NaH (120 mg, 3.00 mmol) was added portion wise. The resulting mixture was stirred at room temperature for 30 min and then treated with 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (234 mg, 1.00 mmol, prepared as described in Example 1, STEP C). The resulting mixture was stirred at room temperature for 2 h and treated with saturated NH4Cl (20 mL) followed by EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated. The resulting residue was dissolved in 1,4-dioxane (10 mL) and treated with 4-methoxybenzylamine (0.650 mL, 5.00 mmol). The resulting mixture was stirred at 65° C. for 2 h. The resulting mixture was allowed to cool to room temperature and then treated with water (10 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated. The resulting residue was purified on silica (0:100-50:50 EtOAc:hexane) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide. 1H-NMR (400 MHz, CDCl3) δ: 8.77 (br. s., 1H), 7.70 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.28-6.36 (m, 1H), 4.59 (d, J=5.1 Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[C:26]([NH2:40])=[CH:27][C:28]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:37][CH3:38])[CH2:31][CH2:30][C:29]=2[CH:39]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:40][C:26]2[C:25]([O:24][CH3:23])=[CH:39][C:29]3[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][O:37][CH3:38])[CH2:33][CH2:34][C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CCN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN([C@@H]1CCCC[C@H]1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl)S(C)(=O)=O

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-ethyl-methanesulfonamide (99 mg, 0.27 mmol), 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (67 mg, 0.27 mmol), and 10-Camphorsulfonic acid (94 mg, 0.40 mmol) in Isopropyl alcohol (4 mL) was heated in a microwave vial for 90 min at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.35 g, 0.94 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-ethyl-methanesulfonamide as an off white foam (70 mg, 40%). LCMS: 581 (M+H); 1H-NMR, CDCl3: 8.18 (s, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 6.64 (s, 1H), 5.86 (s, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.80 (m, 3H), 3.54 (m, 1H), 3.3 (s, 3H), 3.25 (m, 3H), 2.6-2.9 (m, 10H), 2.45 (m, 1H), 1.94 (m, 2H), 1.82 (m, 1H), 1.7 (m, 1H), 1.1-1.5 (m, 7H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:22]I.[C:24]([O:27][CH2:28][CH3:29])(=O)C>CN(C)C=O.O>[CH:28]([O:27][CH:17]([CH3:16])[CH3:12])([CH3:29])[CH3:22].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:24])[C:11](=[O:19])[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Reactant: CI
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(N(C)C(=O)c2ccc(F)cc2)CC1
Product: CC(C)OC(C)C
Reaction time: 0.75 h

Procedure:
To a solution of N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (529 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (0.1 g). After stirring for 45 minutes, methyl iodide (623 ml) was added to the solution. After stirring for 45 minutes, the mixture was diluted with ethyl acetate (100 ml) and water (50 ml). An organic phase was separated, and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After trituration with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-N-methyl-4-fluorobenzamide (248 mg) was obtained.