Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].NC1CCCCC1N.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CCCCCCCCCCCC>O1CCOCC1.O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:6]=1)=[O:4]
Reactant: Brc1ncccn1
Reactant: COC(=O)c1c[nH]cc1C
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cn(-c2ncccn2)cc1C
Temperature: 100 °C
Yield: 69.1 %

Procedure:
333.9 mg (2.4 mmol) 4-methyl-1H-pyrrole-3-carboxylic acid methyl ester, 891.5 mg (4.2 mmol) tri-potassium phosphate, 4 mg (0.02 mmol) CuI, 22 mg (0.2 mmol) 1,2-diaminocyclohexane and 317.9 mg (2 mmol) of 2-bromopyrimidine was suspended in 3 mL of dioxane. After addition of 90 μl of dodecane the mixture was heated in a sealed tube under argon for 12 h at 100° C. The mixture was cooled to room temperature and then diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water (twice), dried over anhydrous sodium sulfate. After filtration the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column flash chromatography (eluent: heptane/dichloromethane/methanol=25/2/1) to obtain 300 mg of 4-Methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[N:5]=[N:6][CH:7]=1.[CH:13](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:3]2[N:12]=[CH:13][N:8]([CH:9]([CH3:10])[CH3:11])[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: CC(C)Nc1nncc(Cl)c1N
Reactant: CCOC(OCC)OCC
Product: CC(C)n1cnc2c(Cl)cnnc21
Temperature: 130 °C
Yield: 76 %

Procedure:
A mixture of 5-chloro-N3-isopropylpyridazine-3,4-diamine (Preparation 5, 1020 mg, 5.47 mmol) in triethyl orthoformate (9 mL) was heated at 130° C. for 80 minutes. The solvent was removed in vacuo and the residue dissolved in MeOH/DCM and purified by silica gel column chromatography eluting with EtOAc:heptane 0-63% to provide the titled product as a white solid in 76% yield, 816 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:12][PH:13](=[O:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:12][P:13]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:14])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2,4-di-(benzyloxycarbonyl)butyl-phosphinic acid (6) (19.3 g, 49.4 mmol) in tetrahydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino pyridine (0.5 g). Dicyclohexylcarbodiimide (DCC, 12 g, 58 mmol) was added and a white precipitate formed. After 30 minutes the white suspension was filtered and the filtrate evaporated under reduced pressure. The clear and colorless oil was purified by flash chromatography and eluted with 1:1 Hexane/EtOAc to give 2,4-di(benzyloxycarbonyl)butylbenzylphosphinic acid (7) (11.5 g, 47%) as a clear and colorless oil. R.function.0.16 (1:1 Hexane/EtOAc).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:5][C:6](=[O:7])[C:8]2[CH:27]=[CH:26][CH:25]=[C:10]([CH2:11][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC3CCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCC1)c1cccc(CN2CCNCC2)c1
Reaction time: 24 h
Yield: 99.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(cyclobutylcarbamoyl)benzyl)piperazine-1-carboxylate (8.84 mmol, 3.3 g) in dichloromethane (10 mL) was added trifluoroacetic acid (5 ml). The reaction mixture was stirred for 24 hours then concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (2.4 g). MS (ESI) m/z 274.5 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5](F)=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]([NH:40][C:35]2[C:34]3[CH:33]=[N:32][N:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:39]=3[CH:38]=[CH:37][CH:36]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Reactant: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Cl)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A solution of 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (75.3 mg, 217 μmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (49.4 mg, 227 μmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with LiHMDS in THF (0.68 mL of 1.0 M solution, 3 equiv.) giving a deep red solution. The mixture was stirred for 45 min and then quenched with water (0.1 mL). Extraction into EtOAc from saturated aqueous NaHCO3, drying (MgSO4) and concentration gave a deep yellow oil. Purification by flash chromatography on silica eluting with 40% EtOAc/hexane gave N-(5-chloro-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (96.8 mg, 82.0% yield) (yellow band on column) as a bright yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.70 (br. s., 1H); 9.82 (d, J=2.74 Hz, 1H); 8.21-8.40 (m, 3H); 8.06 (dd, J=7.53, 1.66 Hz, 1H); 7.42 (t, J=8.02 Hz, 1H); 7.20-7.30 (m, 1H); 5.87 (dd, J=10.47, 2.25 Hz, 1H); 5.72 (dd, J=9.59, 2.54 Hz, 1H); 4.15-4.28 (m, 1H); 4.02-4.12 (m, 1H); 3.70-3.88 (m, 2H); 3.00 (s, 3H); 2.52-2.71 (m, 1H); 1.98-2.27 (m, 5H); 1.58-1.92 (m, 6H). m/z (ESI, +ve) 545.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O.[OH-].[Li+].S(OC)(O[CH3:21])(=O)=O>C1COCC1.C(OCC)C>[CH3:21][O:13][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)cccc1OC
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 6-methylsalicylate (1.27 g, 6.97 mmol) in THF (35 mL) was added lithium hydroxide monohydrate (0.594 g, 14.2 mmol) followed by dimethyl sulfate (1.00 mL, 10.6 mmol). The resultant mixture was heated to reflux for 1 hour then cooled to room temperature. The mixture was diluted with diethyl ether (70 mL), washed with saturated aqueous NaHCO3 (4×10 mL), dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (9:1 hexanes-EtOAc) provided 1.23 g (91%) of ethyl 2-methoxy-6-methylbenzoate as a white solid. 1H NMR (CDCl3) δ1.38 (t, 3H, J=7.2 Hz), 2.30 (s, 3H), 3.82 (s, 3H), 4.40 (q, 2H, J=7.2 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.79 (d, 1H, J=7.8 Hz), 7.23 (dd, 1H, J=7.8, 8.4 Hz).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1cccs1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-thiophen-2-yl-propionic acid to provide the title compound in good yield.
Reaction SMILES: [CH2:1]1[CH:4]([C:5]([OH:7])=[O:6])[NH:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1.Cl>CCOC(C)=O.O.CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N:3]4[CH2:2][CH2:1][CH:4]4[C:5]([OH:7])=[O:6])=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C1CCN1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2ccc(N3CCC3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 6 %

Procedure:
A vial was charged with D,L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL). Then NaH (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456). The heterogeneous white reaction mixture was stirred and heated at 120° C. After overnight stirring the reaction mixture was cooled to rt and was diluted in EtOAc (5 mL). The mixture was poured into a reparatory funnel with 0.5M HCl (1 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane in methanol (9:1) to produce 7.7 mg (6% yield) of 1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (P-446) as a cream solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NC(CO)Cc1c[nH]c2ccccc12
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC(CO)Cc3c[nH]c4ccccc34)cc2c1=O
Yield: 33 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-3-(1H-indol-3-yl)-propan-1-ol according to the GPA affording 18.8 mg (33%) of a red powder. Rt=4.27 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH2:33]([N:35]=C=O)[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:35][CH2:33][CH3:34])=[O:30])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCN=C=O
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Product: CCNC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
By a method similar to Example 17, and using tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate and ethyl isocyanate, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:26])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][N:14]=1)[CH2:6][CH2:5]2.[CH2:27]([CH:30]1[O:32][CH:31]1[CH2:33]O)[CH2:28][CH3:29]>>[F:1][C:2]1[C:3]([O:26][CH2:33][CH:31]2[CH:30]([CH2:27][CH2:28][CH3:29])[O:32]2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][N:18]=1)[CH2:6][CH2:5]2
Reactant: CCCC1OC1CO
Reactant: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3O)C2)nc1
Product: CCCCCCOc1cnc(C2CCc3c(cc(F)c(F)c3OCC3OC3CCC)C2)nc1

Procedure:
From 6,7-difluoro-2-(5-hexyloxypyrimidin-2-yl)-5-hydroxy-1,2,3,4-tetrahydronaphthalene and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12].C(=O)([O-])[O-].[K+].[K+].C>CS(C)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24]([NH:25][C:3]([NH:2][CH3:1])=[S:4])(=[O:27])=[O:26])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12]
Reactant: COc1ccc(F)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
0.26 g (3.5 mmol) of methyl isothiocyanate was added to a suspension of 1.1 g (2.5 mmol) of 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-6-sulfamoyl-chroman and 1.04 g (7.5 mmol) of finely powdered potassium carbonate in 10 ml of DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction and recrystallized from ethanol/DMF. The product had a melting point of 222° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[N:23][C:24]=4[NH:34][NH2:35])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:37]([OH:38])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 95 °C

Procedure:
To a round bottom flask was added tert-butyl{1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (2.77 g, 5.75 mmol), and 1,1′-carbonylbis(1H-imidazole) (4.10 g, 4.40 mmol), in 1,4Dioxane (30 mL). The sealed reaction mixture was then heated at 95° C. under an atmosphere of nitrogen. To the crude reaction mixture was added a saturated solution of sodium bicarbonate (100 mL) and ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography eluting with 0-10% IPA/DCM. The appropriate fractions were then combined and the solvent was removed in vacuo to give tert-butyl{1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6a) as a tan solid. MS (M+H)+: observed=508.1, calculated=508.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH2:19]([N:21]([CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CC)CCCCNC
Product: CCN(CC)CCCCN(C)c1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and N1,N1-diethyl-N4-methylbutane-1,4-diamine, the title compound was obtained; MS (Found M+1=400).
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[N:19]([C:20](=[O:22])[CH:21]=2)[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[NH:16]3)=[CH:9][CH:8]=1>>[F:4][CH2:3][CH2:2][N:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]2[C:20](=[O:22])[CH:21]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=3)[CH:14]=[C:15]12
Reactant: FCCBr
Reactant: COc1ccc(-c2cc(=O)n3c(c2)[nH]c2ccccc23)cc1
Product: COc1ccc(-c2cc(=O)n3c4ccccc4n(CCF)c3c2)cc1

Procedure:
General experimental procedure (E) for N-alkylation reaction with 1-bromo-2-fluoroethane was followed. Reaction was performed on a 10.0 mg scale of 3-(4-methoxyphenyl)-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole. Isolated 3.8 mg (33%) of T626 as a white solid. 1H NMR (CDCl3): δ 8.84 (1H, d, J=8.0 Hz), 7.62 (2H, m), 7.45 (1H, m), 7.31 (2H, m), 6.97 (2H, m), 6.54 (1H, s), 6.28 (1H, s), 4.90 (1H, t, J=4.8 Hz), 4.79 (1H, t, J=4.8 Hz), 4.52 (1H, t, J=4.8 Hz), 4.46 (1H, t, J=4.8 Hz), 3.84 (3H, s); MS: 337 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:31]1[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 4-trifluoromethoxy-phenylboronic acid (64 mg, 0.31 mmol), K3PO4 (87 mg, 0.41 mmol), H2O (7.4 mg, 0.41 mmol), SPhos (4.2 mg, 0.010 mmol) and Pd(OAc)2 (4.2 mg, 0.0062 mmol) in toluene (5 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., water (10 mL) and EtOAc (30 mL) were added. 1 M HCl was added with stirring until pH was about 2, and the organic layer was washed with brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (5% EtOAc/CH2Cl2) to give 36 mg of the title compound. MS: (+) m/z 471.27 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[N:4]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(I)c3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 3-iodo-5-(6-isopropoxy-pyrazin-2-yl)-1H-indole (20 g, 0.053 mol) in DMF (200 mL) was added NaH (6.5 g, 0.158 mol) slowly at 0° C., and then stirred for 15 min. p-Toluenesulfonyl chloride (15.10 g, 0.079 mol) was added slowly to the reaction mixture and stirred for 1 h. The resulting mixture was poured into ice with stirring and the precipitate was formed. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the crude product. The crude product was purified by column chromatography eluting with EtOAc and n-hexane to afford the desire 3-iodo-5-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indole (15.5 g, 55%) as pale brown solid. MS (ESI, m/z): 533.6 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]2[CH:16]=[N:17][NH:18][C:6]=12)[CH:2]=[CH2:3].[CH3:19][O:20][C:21](OC)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:16][N:17]([C:21]([O:20][CH3:19])([CH3:23])[CH3:22])[N:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCNc1c(C(=O)OCC)cnc2cn[nH]c12
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCNc1c(C(=O)OCC)cnc2cn(C(C)(C)OC)nc12
Yield: 64.3 %

Procedure:
A mixture of ethyl 7-allylamino-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate (3.69 g, 15 mmol), 2,2-dimethoxypropane (9.2 ml, 75 mmol) and 4-toluenesulphonic acid (142 mg, 0.75 mmol) in acetone (200 ml) was heated under reflux for 48 h. The solution was cooled and stirred with solid potassium carbonate, then filtered and evaporated in vacuo. Column chromatography of the residue on basic alumina (100 g), eluting with ethyl acetate, gave the title compound as a white solid (3.07 g, 64%), m.p. 102°-103° C. Found: C, 60.31; H, 6.78; N, 17.60; C16H22N4O3 requires C, 60.36; H, 6.97; N, 17.60%
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[I-]>O.C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 6 h

Procedure:
To 0.34 mg fluorescein isothiocyanate placed as a dry solid in a screw-capped test tube was added 64 micrograms of N,N,N-trimethylammoniumbenzene iodide in 25 microliters of water, 0.2 ml 1M sodium carbonate buffer, pH 9.5, and 17 mg of the antibody product obtained in Example 3 in 2 ml PBS. The reaction was continued for six hours on ice, after which the solution was dialyzed against 0.015M NaCl, 0.01M sodium phosphate. This solution was applied to a DEAE-cellulose column equilibrated in the same buffer. Step-wise increases in NaCl concentration gave fractions eluting between 0.05M NaCl and 0.15M NaCl which were pooled and dialyzed against PBS. The solution was sterilized by passage through a 0.2 micron filter to yield a fluorescein labeled antibody.