Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([S:42][CH2:43][CH2:44][NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CCO>[CH2:17]([N:13]1[C:14]2=[CH:15][N:45]([CH2:44][CH2:43][S:42][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]1=[O:19])[CH3:18]
Reactant: CCn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(CC)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-diethylpyrimidine-2,4(1H,3H)-dione (step 3) (850 mg, 2.327 mmol), 2-(tritylthio)ethanamine (commercially available, 1115 mg, 3.49 mmol) and triethylamine (0.973 mL, 6.98 mmol) were combined in EtOH (Volume: 20 mL) and the mixture heated at reflux for 20 mins. The reaction mixture was cooled to RT and evaporated under vacuum. The residue was partitioned between DCM and water and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and purification by chromatography on silica eluting with 10-50% EtOAc in iso-hexane afforded the title compound as a white solid;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
Example 18 was prepared in accordance to a procedure described in Collins, et. al., Tetrahedron, 48, No. 37, pp 7887-7898, 1992. To a solution of 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added 1-Methyl-piperazine (0.64 mL, 5.74 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS: The reaction was filtered and concentrated before being taken up in CH2Cl2 and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.
Reaction SMILES: CN1CCOCC1.CN(C(O[N:16]1N=N[C:22]2[C:17]1=[CH:18]C=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:38]=[C:37]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48](O)=[O:49])(=[O:41])=[O:40])[CH:36]=[CH:35][C:34]=1[NH:51][C:52](=[O:60])[C@:53]([OH:59])([CH3:58])[C:54]([F:57])([F:56])[F:55].CC(N)C>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[C:37]([S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([NH:16][CH:17]([CH3:22])[CH3:18])=[O:49])(=[O:40])=[O:41])[CH:36]=[CH:35][C:34]=1[NH:51][C:52](=[O:60])[C@:53]([OH:59])([CH3:58])[C:54]([F:56])([F:55])[F:57]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2C(=O)O)cc1Cl)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1ccccc1S(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
N-Methylmorpholine (1.22 ml) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.092 g) were added to a solution of (R)-N-[2-chloro-4-(2-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 125) (0.10 g) and 2-propylamine (0.024 ml) in DCM (20 ml) at (0° C. The reaction mixture was stirred at this temperature for 30 minutes then allowed to warm to room temperature, stirred for a further 3 hours then evaporated to dryness. The residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 50% ethyl acetate/hexane then triturated with ether/hexane to give the title compound (0.05 g) as a solid. NMR (CDCl3): 1.3 (d, 6H), 1.6 (s, 3H), 4.2-4.32 (m, 1H), 5.8 (brd, 1H), 7.4 (d, 1H), 7.5-7.7 (m, 3H), 7.9 (dd, 1H), 8.05-8.13 (m, 2H), 8.6 (d, 1H), 9.3 (brs, 1H); MS (ESP−): 491.
Reaction SMILES: [N:1]1([CH2:8][C:9]2[S:10][C:11]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[OH:19][C:18]1[O:15][C:14]([C:11]2[S:10][C:9]([CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][CH:12]=2)=[N:16][N:17]=1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Yield: 94.6 %

Procedure:
760 mg (3.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide was dissolved in 30 ml of tetrahydrofuran and 3 ml of N,N-dimethylformamide, 583 mg (3.6 mmol) of 1,1'-carbonyldiimidazole and 0.84 ml (6.0 mmol) of triethylamine were added, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 793 mg of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([CH2:32][CH2:33][CH2:34][OH:35])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@@:18]([CH2:32][CH2:33][CH2:34][O:35][S:37]([CH3:36])(=[O:39])=[O:38])([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:19]1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)N1CCCC(CCCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Diisopropylethylamine (1.6 mL, 9.18 mmol) was added to a solution of alcohol (10) (1.2 g, 3.06 mmol 3.0 eq) in CH2Cl2 (30 mL) followed by MsCl (0.28 mL, 3.67 mmol, 1.2 eq). The solution was stirred at room temperature for 2 hours, then quenched with water and diluted with CH2Cl2 (200 mL). The organic layer was washed with brine, 1N HCl, saturated NaHCO3, and dried over MgSO4. The crude oil was purified by flash chromatography (CH2Cl2—MeOH/95:5) to give light yellow solid (1.43 g, 99.3%).
Reaction SMILES: O=[C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14](CC(O)=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[C:25](Cl)(=O)[C:26]([Cl:28])=[O:27].C(Cl)(Cl)[Cl:32]>CN(C=O)C>[Cl:32][C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([CH2:25][C:26]([Cl:28])=[O:27])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetic acid (8.83 g, 27.7 mmol) was suspended in 175 mL of chloroform. Twenty drops of DMF were added followed by oxalyl chloride (7.2 mL, 83.0 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and concentrated under reduced pressure at 40° C. to afford crude (4-chloro-2-phenyl-2H-pyrazolo[3,4-c]quinolin-1-yl)acetyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH:46]2[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]2)=[C:39]2[C:43]=1[C:42](=[O:44])[N:41]([CH3:45])[CH2:40]2>>[OH:52][C@H:49]1[CH2:50][CH2:51][C@H:46]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:33]=[CH:32][C:16]([CH2:17][P:18](=[O:31])([O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:15][CH:14]=4)[N:3]=3)=[C:43]3[C:39]=2[CH2:40][N:41]([CH3:45])[C:42]3=[O:44])[CH2:47][CH2:48]1
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Reactant: O=P(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)(OCC(F)(F)F)OCC(F)(F)F
Product: CN1Cc2c(c(Nc3nc(Nc4ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc4)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O

Procedure:
The title compound was prepared according to the procedure from Example 102 using bis(2,2,2-trifluoroethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 165A, 35.7 mg, 0.0671 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (18.5 mg, 0.0711 mmol). The crude material was first purified on a Teledyne/ISCO system eluting with 50-100% EtOAc:Heptane followed by MDP (under acidic conditions; formic acid). The desired fractions were collected and concentrated in vacuo, giving the title material as an off-white solid, 24.3 mg (47%, 0.0315 mmol). 1H NMR (400 MHz, DMSOd6) δ ppm 10.59 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.15-9.25 (m, 1H), 7.63 (d, J=6.1 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (dd, J=8.6, 2.5 Hz, 2H), 4.58-4.72 (m, 5H), 4.53 (s, 2H), 3.43-3.61 (m, 3H), 3.08 (s, 3H), 1.94 (dd, J=11.7, 2.1 Hz, 2H), 1.77 (d, J=11.6 Hz, 2H), 1.56 (dtd, J=12.9, 12.7, 2.1 Hz, 2H), 1.21-1.37 (m, 2H). MS (ES+): m/z 756.16 (100) [MH+]. HPLC: tR=4.14 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Product: CC(C)(C)c1c[nH]c2cc(N)ccc12
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney Nickel (0.5 g) was hydrogenated under H2 (1 atm) at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel (petroleum ether/ethyl acetate=4:1) to give 3-tert-butyl-1H-indol-6-amine (2.0 g, 77%) as a gray solid. 1H NMR (CDCl3) δ 7.58 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J=0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]=1[O:20][CH3:21].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:21][O:20][C:5]1[C:6]([O:16][CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=1[CH2:3][CH:2]=[O:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.3 Grams (4.3 mM) of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was dissolved in 15 ml of dichloromethane, then under ice-cooling condition, 1 g of pyridinium chlorochromate was added thereto and the reaction mixture was stirred at a room temperature for 10 hours. After filtration, the filtrate was concentrated under a reduced pressure, and the residue obtained was treated by a silica gel column chromatography (diameter 3 cm×length 15 cm, eluent: 30% ethyl acetate: n-hexane, "Wakogel C-200") to yield 1 g of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde. Colorless oily substance.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]([C@H:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)[CH3:13].[CH2:20](I)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C@@H:15]1[C@@H:14]([CH:12]([CH3:13])[CH3:11])[CH2:19][O:18][C:16]1=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H]1COC(=O)C1
Reactant: ICc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 92 mL, 92 mmol) was added in 3 to 5 minutes to a solution of (S)-β-(2-propyl)-γ-butyrolactone 175 (11.68 g, 91.25 mmol) in dry THF 100 mL at −78° C. under argon atmosphere. It was stirred for 1 hour and a solution of benzyl iodide (21.87 g, 100.37 mmol) in dry THF was added rapidly. Stirring was continued for 1.5 hours and quenched at −78° C. by the addition of a solution of brine followed by ethyl acetate. The organic phase was separated and the aqueous was further extracted with ether. Chromatography on silica gel first eluted with 5% methylene chloride in pet ether, and finally with 10% ether in pet ether gave desired compound 11.6 g, 58%. NMR (CDCl3) δ 7.19 (m, 5H, C6H5), 4.02 (app. t, 1H, CHaHbO), 3.87 (dd, 1H, CHaHbO), 2.98 (d, 2H, ArCH2), 2.57 (q, 1H, BnCHC═O), 2.05 (m, 1H, CHCH(Me)2, 1.55 (m, 1H, CH(Me)2), 0.81 (d, 3H, CH3) and 0.72 (d, 3H, CH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:16][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[F:15])[N:5]([CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20][CH2:19]1)[C:6](=[O:17])[CH2:7][CH2:8]2
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Reactant: CC(C)(C)C(=O)OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethyl-propionic acid 2-piperidin-4-yl-ethyl ester, and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (21 mg, 48 μmol, 24%). 1H NMR (CD3OD) d 7.23-7.12 (m, 2H), 4.11 (t, J=6.0 Hz, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.18-3.06 (m, 2H), 2.88 (br t, 6.8 Hz, 2H), 2.66-2.58 (m, 4H), 2.29 (dt, J=2.0, 12.0 Hz, 2H), 1.94-1.85 (m, 2H), 1.81 (br d, J=13.6 Hz, 2H), 1.64-1.57 (m, 2H), 1.57-1.45 (m, 1H), 1.42-1.31 (m, 2H), 1.18 (s, 9H); 13C NMR (CD3OD) d 178.9, 171.1, 149.2 (dd, J=13, 241 Hz) 145.8 (dd, J=13, 230 Hz), 135.0 (br), 123.8 (dd, J=4, 6 Hz), 116.5 (d, J=19 Hz), 105.1 (d, J=23 Hz), 62.2, 55.0 53.2, 40.2, 38.6, 34.7, 31.1, 30.8, 26.4, 24.3, 23.5; HPLC-MS (ammonium acetate) [M+H]+=437.22.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][C:21]1[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1>CCOCC.CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: Cn1cccc1CCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cn1cccc1CCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 3.5 h
Yield: 79.5 %

Procedure:
250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (Alt-0027) and 400 mg (3.22 mmol) of 2-(2-aminoethyl)-1-methyl-pyrrole were heated together in a 10 ml round bottom flask with stirring (no solvent) at 110°-120° C. for 3.5 hours. The dark viscous residue was treated with a 1:1 mixture of ether/acetone and stirred vigorously for 30 minutes. The precipitate was collected by filtration and was washed with ether and acetone and dried in vacuo to yield 265 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1-methylpyrrol-2-yl)ethyl] propanamide (AIT-0035) as an off-white solid. Yield: 80%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.62 g, 18.1 mmol, 1.2 equiv) in dry DMF (20 mL) under Ar was added sodium hydride (0.99 g, 22.7 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 4,7-dichloro-quinazoline (3.0 g, 15.1 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 30 min. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (10:1→1:1) afforded 4-(7-chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 79%). 1H NMR (300 MHz, CDCl3): δ 1.42-1.53 (m, 2H), 1.48 (s, 9H), 2.16-2.18 (m, 2H), 2.92-2.98 (m, 2H), 4.17-4.20 (m, 2H), 4.39-4.49 (m, 1H), 5.79 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.8 Hz, J=2.1 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 8.63 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 28.50, 32.05, 42.89, 48.38, 79.85, 113.29, 122.11, 126.75, 127.89, 138.70, 150.65, 154.78, 156.37, 158.58. MS (ISP): 363.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([N:28](CC)CC)[CH3:27].[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:28][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:27])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCN(CC)CC
Reactant: c1ccccc1
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.10 g, 2.75 mmol), S-(-)-1-phenylethylamine (0.400 g, 3.30 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.945 g, 70.9% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:2].[CH3:21][CH2:22][N:23](CC)[CH2:24][CH3:25].F[P-](F)(F)(F)(F)F.[N:35]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:39]2[CH:40]=[CH:41][CH:42]=CC=2N=N1>C(Cl)Cl>[CH:39]1([N:35]2[CH2:25][CH2:24][N:23]([C:8]([C:7]3[N:3]([CH2:1][CH3:2])[C:4]([C:11]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=[CH:13][CH:12]=4)=[N:5][CH:6]=3)=[O:9])[CH2:22][CH2:21]2)[CH2:40][CH2:41][CH2:42]1
Reactant: CCn1c(C(=O)O)cnc1-c1cccc2ccccc12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN(CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(=O)N2CCN(C3CCC3)CC2)cnc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid (105 mg, 0.394 mmol) and 1-cyclobutylpiperazine bistrifluoroacetate (145 mg, 0.394 mmol, 1.0 eq.) are dissolved in DCM (5 ml), and to the solution is added Et3N (4 eq.), followed by BOP coupling regent (183 mg, 0.433 mmol, 1.1 eq.). The resulting mixture is stirred at rt overnight. DCM is evaporated, and the residue is taken up in EtOAc (1.0 ml). The solution is washed thoroughly with water (3.0 ml×3) to remove the by-product from BOP, and then washed with brine. The solution is dried over sodium sulfate, concentrated and purified through PTLC to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.98 (1H, m), 7.92 (1H, dd), 7.44˜7.63 (5H, m), 7.39 (1H, s), 4.05 (2H, q), 3.89 (4H, s, br), 2.80 (1H, m), 2.43 (4H, s, br), 1.50˜2.20 (6H, m), 1.09 (3H, t); LCMS 389 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>C1COCC1.[Ni]>[CH2:1]([O:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(N)c(OCc2ccccc2)n1
Yield: 54.7 %

Procedure:
2-Benzyloxy-6-methoxy-3 nitro-pyridine (3.41 g, 13.1 mmol) was shaken with 1 g Rainey nickel in 100 mL THF in a Parr hydrogenation apparatus at 48 psi H2 for 20 h. TLC analysis (silica, CH2Cl2) indicated complete consumption of starting material. The reaction mixture was filtered and concentrated. The crude product was purified by gradient elution flash chromatography (SiO2, 1:1 CH2Cl2/hexanes to 3:1 CH2Cl2/hexanes to 100% CH2Cl2) to give 1.65 g (7.17 mmol, 55%) of 2-benzyloxy-6-methoxy-pyridin-3-ylamine. MS (APCI) m/z 231.2 (M+1). 1H NMR (300 MHz) CDCl3 7.29-7.48 (m, 5H), 6.98 (d, J=8.1 Hz, 1H), 6.19 (d, J=8.1 Hz, 1H), 5.42 (s, 2H), 3.84 (s, 3H).