Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14].N1C=CC=CC=1.[Cl:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>ClCCl>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:14][C:24](=[O:25])[CH:23]([Cl:22])[CH3:27]
Reactant: COC(=O)CCN
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCNC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Triethylamine (1.63 g) was added to a suspension of β-alanine methyl ester hydrochloride (2.25 g) in dichloromethane (10 mL) and the reaction mixture was stirred for 30 minutes. After addition of pyridine (1.27 g) the reaction mixture was cooled to 0° C. A solution of 2-chloropropionyl chloride (2.04 g) in dichloromethane (10 mL) was added dropwise for 20 minutes. The reaction mixture was stirred for 2 hours, washed sequentially with water, 1 N hydrochloric acid and saturated sodium bicarbonate, dried with magnesium sulfate, filtered, and concentrated to give yellow oil (2.9 g, yield 93%).
Reaction SMILES: I[CH2:2][CH3:3].[Cl:4][C:5]1[C:14]2[C:13](=[O:15])[NH:12][C@H:11]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:10]3[C:9]=2[CH:8]=[C:7]([CH2:26][CH3:27])[CH:6]=1>>[ClH:4].[Cl:4][C:5]1[C:14]2[C:13](=[O:15])[N:12]([CH2:2][CH3:3])[C@H:11]3[CH2:16][NH:17][CH2:18][C@@H:10]3[C:9]=2[CH:8]=[C:7]([CH2:26][CH3:27])[CH:6]=1
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Reactant: CCI
Product: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1N(CC)C2=O
Product: Cl

Procedure:
Following the procedures described in Example 24, Parts A and B, except that iodoethane was used instead of iodomethane, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-ethyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from the OD column separation of N-BOC intermediate enantiomers in Example 29 and 30 (the first eluting compound gave Example 29), was converted to the title compound of Example 41 as an off-white solid. 1H NMR (CD3OD): δ 7.28 (s, 1H), 7.22 (s, 1H), 4.43-4.37 (m, 1H), 3.88-3.81 (m, 1H), 3.73-3.68 (m, 1H), 3.69 (q, 2H), 3.63 (dd, 1H, J=7.8, 12.3 Hz), 3.45-3.38 (m, 1H), 3.26-3.20 (m, 1H), 2.61 (q, 2H, J=7.5 Hz), 1.17 (t, 3H, J=7.7 Hz), 1.14 (t, 3H, J=7.5 Hz). LRMS (ESI): 279.2/281.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[CH:18]1([NH:22][S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([NH:22][S:23]([N:4]2[C:3]3([CH2:1][CH2:2]3)[CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5]2)(=[O:25])=[O:24])[CH2:21][CH2:20][CH2:19]1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: O=S(=O)(Cl)NC1CCC1
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (6.55 mmol) (intermediate 21) in dry pyridine (25 mL) was added N-cyclobutylsulfamoyl chloride (7.86 mmol) (Intermediate 29). The reaction mixture was stirred at rt for 16 h. After evaporation of the solvent in vacuo the crude mixture was purified by flash chromatography on silica using heptane→MeOH:EtOAc affording the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH2:34])[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([NH:34][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c2nc(Br)cnc21
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In a 100 mL round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.0 g, 2.69 mmol) was combined with dichloromethane (3 ml) to give a yellow solution. (R)-1-Benzylpyrrolidin-3-amine (710 mg, 4.03 mmol) and then DIEA (1.88 ml, 10.7 mmol) were added. To the clear solution was added HATU (2.04 g, 5.37 mmol) and to this mixture was added DMF (4 ml). The reaction was stirred under nitrogen overnight then concentrated and partioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was washed with EtOAc (50 ml) then the combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude was dissolved in EtOAc, supported on silica gel, and purified by flash chromatography (120 g silicycle) with 0% to 100% EtOAc in hexanes. The appropriate fractions combined and concentrated to yield 1.38 g (97%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a clear viscous semisolid with a slight red/brown tint. LC-MS (M+H)+=530.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H:23]2[C@@H:14]([CH2:15][N:16]3[C@H:21]([CH2:22]2)C2NC4C=C(OC)C=CC=4C=2CC3)[CH2:13][C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O.C(#[N:55])C>>[F:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:15]2[N:16]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]#[N:55])=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Reactant: Oc1ccc(F)nc1
Product: N#Cc1cccnc1Oc1ccc(F)nc1

Procedure:
The title compound was synthesized according to General Procedure 9 using 2-fluoro-5-hydroxypyridine. 1H NMR (DMSO-d6, 400 MHz) δ 7.33 (dd, 1H, J=3.3 Hz, J=8.8 Hz), 7.37 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 8.01 (ddd, 1H, J=3.0 Hz, J=6.7 Hz, J=8.9 Hz), 8.26 (dd, 1H, J=1.6 Hz, J=2.9 Hz), 8.40 (dd, 1H, J=1.9 Hz, J=5.0 Hz), 8.47 (dd, 1H, J=1.9 Hz, J=7.6 Hz); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt 3.67 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[S:7]1[C:11]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[S:7]1[C:11]2[CH:12]=[C:13]([NH:16][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[O:6])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCCCl)Nc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
1-Chloro-2-isocyanato-ethane (2.1 g, 19.99 mmol) was added drop wise to a stirred solution of benzothiazol-6-ylamine (2 g, 13.33 mmol) in toluene (80 mL) over a period of 15 minutes at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 2.73 g (80.2% yield) of 1-benzothiazol-6-yl-3-(2-chloro-ethyl)-urea.
Reaction SMILES: O.C(O)C.[CH:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:11]1[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[C:14]([C:28]([O:30]CC)=[O:29])=[CH:13][N:12]=1)[CH2:6]2.[OH-].[Na+]>C1COCC1>[CH:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:11]1[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[C:14]([C:28]([OH:30])=[O:29])=[CH:13][N:12]=1)[CH2:6]2
Reactant: CCOC(=O)c1cnc(N2CC3CC3C2)nc1NCc1ccc(OC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1F
Reaction time: 5 h
Yield: 41.5 %

Procedure:
In the mixture of water (5 mL), ethanol (5 mL) and THF (15 mL) were dissolved ethyl 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylate (1.5 g, 3.9 mmol) and sodium hydroxide (260 mg, 6.5 mmol). The reaction was conducted at ambient temperature for 5 h. The solvent was removed by evaporation, followed by addition of water and washing with DCM. The aqueous phase was adjusted to a pH of 2 with dilute hydrochloric acid, and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid as a faint yellow solid (580 mg, 41.5% yield).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]2[C:25](=[O:26])[N:8]3[C:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]23)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C1C[O:36]CC1.[OH-].[Na+].O>C(OCC)(=O)C>[C:1]([C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]12)=[O:27])([OH:36])=[O:32]
Reactant: C1CCOC1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A solution of 458 mg. (1 mmol.) of t-butyl 7-phthalimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml. of THF was cooled in an ice water bath, and 1.1 ml. of 1N NaOH were then added. After stirring for 5 min., 10 ml. of water and 30 ml. of ethyl acetate were added. The ethyl acetate layer was separated, and 70 mg. of starting material were recovered therefrom. The aqueous layer was acidified to pH 4.0, and the acidified layer was extracted with ethyl acetate. After workup, 330 mg. (83%) of the desired phthalamic acid were obtained [α] + 26.37 (MeCN); λEtOH 260 mμ (ε 8800)D ; ir (CHCl3) 1785, 1730 and 1685 cm-1 ; nmr (CDCl3) δ 1.55 (s, 9, t-Bu), 2.05 (s, 3, Ac), 3.3 and 3.6 (ABq, 2, J = 17 Hz), 4.72 and 5.2 (ABq, 2, J = 14 Hz), 4.98 (d, 1, J = 4.5 Hz), 5.9 (dd, 1, J = 4.5 and 9 Hz), and 7.5-8 (m, 4, ArH).
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:9]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[N:10][C:11]([Br:18])=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:18][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:8]2[NH:5][C:20]3=[N:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:23][CH:24]=[C:19]3[C:9]=2[N:10]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCCCCCCC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1nc(N3CCOCC3)ccc12
Temperature: 80 °C
Yield: 74.7 %

Procedure:
1,2-Dichloroethane (0.4 mL) was added to a mixture of methyl 3-azido-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (240 mg, 0.572 mmol), rhodium octanoate dimer (35.7 mg, 0.046 mmol) and crushed 4 A° molecular sieves (500 mg gm) and heated overnights at 80° C. The reaction was diluted with THF and filtered. The collected solid was washed with multiple portions of boiling THF to extract all of the product. The solvent was removed from the combined filtrates and the residue was suspended in MeOH and the product was collected by filtration. This left methyl 2-bromo-7-(4-morpholinyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (167 mg, 0.427 mmol, 745% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.75 (1H, s), 8.30 (1H, d, J=8.85 Hz), 7.72 (1H, s), 6.91 (1H, d, J=8.85 Hz), 4.01 (3H, s), 3.74 (8H, dd, J=15.56, 4.88 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[C:28]([Cl:40])[CH:27]=3)=[N:24][N:23]=[N:22]2)C=CC=CC=1>>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][C:28]([Cl:40])=[CH:27][C:26]=4[C:25]4[NH:21][N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[ClH:40]
Reactant: Clc1ccc(-c2ccc(CBr)cc2)c(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccc(Cl)cc2-c2nnn[nH]2)cc1
Product: Cl

Procedure:
The title compound was prepared from 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine and N-triphenylmethyl-5-(4'-bromomethyl-4-chlorobiphen-2-yl)tetrazole in a manner similar to Example 7, and was isolated as an HCl salt.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:13]=[C:12]([C:24](=[NH:27])[NH:25]O)[N:11]=1.C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:13]=[C:12]([C:24]2[N:27]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:8][N:25]=2)[N:11]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N=C(NO)c1nc(N)nc(Nc2cccc(F)c2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2nc(N)nc(Nc3cccc(F)c3)n2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
Ethyl chlorooxoacetate (0.12 g, 0.84 mmol) was added to a mixture of (4-amino-6-[(3-fluorophenyl)amino]-N-hydroxy-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 97, 0.20 g, 0.76 mmol) in pyridine (0.12 mL) and toluene (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and at 110 C for 3 h. The mixture was then cooled at room temperature; DCM (20 mL) and 1M aq. HCl (50 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (2×20 mL). The organic extracts were combined, dried over sodium sulfate, and concentrated. The crude residue was washed with diethyl ether. The organic filtrate was concentrated and purified by flash chromatography to afford the title compound as a yellow solid (45 mg, 17%). Method D HPLC-MS: MH+ requires m/z=346 Found: m/z=346, Rt=2.70 min (40%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:27]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:16])[CH2:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)N1c2cc(C)c(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1c2cc(C)c(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC([C@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.87 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH2:12].[OH2:13].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[C:8]([OH:13])=[O:12]
Reactant: O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
2-chloro-4-methyl-5-nitropyridine (1.0 g, 5.8 mmol) was cooled using an ice water bath. Sodium dichromate dihydrate (3.45 g, 11.6 mmol) dissolved in sulphuric acid (50 mL) was added dropwise, ensuring reaction temperature does not exceed 15° C. After complete addition, reaction allowed to warm to room temperature and stirred overnight. Quenched with ice, extracted into ethylacetate and concentrated under reduced pressure to afford 2-chloro-5-nitroisonicotinic acid (1.3 g, 6.4 mmol).
Reaction SMILES: C[CH:2]([C:8]([CH3:10])=[O:9])[C:3](OCC)=[O:4].[C:11]1([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[O-][CH2:25]C.[Na+]>>[CH:11]1([CH:17]2[C:18]([CH3:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3](=[O:4])[CH2:2][C:8](=[O:9])[CH2:10]2)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: CCOC(=O)C=CC1=CCCCC1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1(C)C(=O)CC(=O)CC1C1CC=CCC1

Procedure:
To a cooled solution of sodium ethoxide (from 2.3 g. sodium and absolute ethanol, 30 ml.) was added with shaking ethyl 2-methylacetoacetate (14.2 g.). When homogeneous the mixture was treated with ethyl 3-(cyclohexenyl)acrylate (16.8 g.) and then heated under reflux for 18 hrs. After cooling the mixture was diluted with 500 ml. water and extracted with ether and the extracts discarded. The aqueous solution was then acidified with 2N-hydrochloric acid and extracted with ether. After washing the ether solution with water and drying over Na2SO4, evaporation of the solution afforded ethyl 6-(3-cyclohexenyl)-2,4-dioxo-1-methylcyclohexanecarboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(Cl)(=[O:12])C.[Cl:14][CH2:15][CH2:16]Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:12]
Reactant: ClCCCl
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccccc21
Reaction time: 3 h
Yield: 85 %

Procedure:
A quantity of 2,3-dihydro-1H-1-indole (also known as indoline, 2.1 g, 17.6 mmol) is dissolved in toluene (60 ml). To the solution of the amine in toluene is added acetyl chloride (2.0 g, 17.6 mmol) dissolved in 1,2-dichloroethane (20 ml). The reaction mixture turns brown upon addition of the acid chloride. The reaction is allowed to proceed at room temperature, with stirring, for about 3 hr, after which the reaction mixture is diluted with ethyl acetate and washed with 50:50 (v/v) water:saturated NaCl solution (2 times). The organic phase is dried over anhydrous MgSO4 and concentrate to yield 2-Chloro-1-(2,3-dihydro-1H-1-indolyl)-1-ethanone (may also be named 2-chloro-1-indolinylethan-1-one) in 85% yield (2.92 g, 15 mmol) as a light brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH2:43][CH2:44][CH2:45]C)[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].[C:47](O)(=O)C>ClCCl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH2:43][CH:44]([CH3:45])[CH3:47])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: CCCC[C@H](N)CCNCC(C)C
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1CCN(CC(C)C)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 25 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based. [(3S)-3-amino-6-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 25%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m, 5H), 1.76-1.82 (m, 1H), 2.05-2.09 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.55-4.66 (m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES+ MS: 499 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:12]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:24][CH:25]=3)=[CH:18][N:17]([CH:27]([CH3:29])[CH3:28])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CC(C)n1cc(-c2ccc(N)cc2)c2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1cc(-c2ccc(NC(=O)c3ccccc3)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Benzoyl chloride (101 mg) in dichloromethane (1.0 ml) was added to a mixture of 4-amino-5-(4-aminophenyl)-7-isopropylpyrrolo[2,3-d]pyrimidine (175 mg), in dichloromethane (7 ml) and triethylamine (73 mg) at 0° C. under nitrogen with stirring. The mixture was stirred at 0° C. for four hours and then allowed to warm up to ambient temperature over one hour. The reaction mixture was stirred at ambient temperature for 18 hours and then quenched by the addition of saturated sodium bicarbonate solution (10 ml) with ice-cooling. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water, dried and evaporated to give a pale yellow solid which was purified by preparative HPLC to give N-(4-{4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-benzamide, m.p. 192-195° C.