Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:34]([CH3:35])=[C:33]([CH3:36])[C:12]2[N:13]([CH3:32])[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)=[N:15][C:11]=2[C:10]=1[CH3:37]>>[C:1]([O:8][C:9]1[C:34]([CH3:35])=[C:33]([CH3:36])[C:12]2[N:13]([CH3:32])[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)=[N:15][C:11]=2[C:10]=1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)c(C)c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1C
Product: CC(=O)Oc1c(C)c(C)c2c(nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n2C)c1C
Reaction time: 3 h

Procedure:
0.032 ml of acetic anhydride were added at room temperature to a solution of 0.12 g of 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 3) in 2 ml of pylidine, and the resulting mixture was stirred for 3 hours, after which it was allowed to stand overnight. At the end of this time, the reaction mixture was freed from the solvent by evaporation under reduced pressure, and the resulting residue was mixed with water. The aqueous mixture was then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, after which the solid residue was triturated with diethyl ether and collected by filtration. It was then washed with diethyl ether, to give 0.12 g of the title compound, melting at 250°-253° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>>[CH3:12][C:11]1[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][CH2:22]2)=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1nc2ccccc2nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2ccccc2nc1N1CCN(Cc2ccccc2)CC1
Temperature: 125 °C

Procedure:
2-Chloro-3-methylquinoxaline (1.0 g, 5.6 mmol) and N-benzylpiperazine (2.9 ml, 16.8 mmol) were mixed and heated to 125° C. for 18 h. Saturated aqueous sodium hydrogen carbonate was added and the product was extracted with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a dark red oil. The crude product was purified by flash chromatography using silica gel eluting with methanol:dichloromethane (15:85) to give the pure product as a red oil which solidified upon standing (1.63 g, 94%).
Reaction SMILES: C[Mg]I.[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[N:14]=[CH:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].[CH2:19]1COCC1.[Cl-].[NH4+]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[C:15]([CH:17]([OH:18])[CH3:19])[N:14]=[CH:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: C1CCOC1
Reactant: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of methylmagnesium iodide in ether (3 M, 13,7 ml, 41.1 mmol) and ether (40 ml), 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carbaldehyde (2.58 g, 10.7 mmol) was added in portions. THF (50 ml) was then added slowly and stirring was continued for 1 h at reflux. After the addition of aqueous ammonium chloride (saturated, 30 ml), the mixture was extracted with AcOEt. The organic phase was dried (Na2SO4) and evaporated to give 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanol (2.56 g, 93%) as a light brown solid. MS: m/e=257.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:27][CH2:28]OS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[C:11]([S:22][CH2:27][CH2:28]3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCS3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred slurry of 3.1 g (0.01 mole) 4,5 bis-(p-methoxyphenyl)-2-mercaptoimidazole [Anschutz and Schwickerath, Ann., 284, 24 (1895)] in 50 ml methanol was added 0.65 g (0.012 mole) of sodium methoxide. To the resulting solution was added 2.6 g (0.011 mole) 2-chloroethyl-p-toluenesulfonate in 10 ml methanol. The mixture was heated at reflux overnight. Another 0.5 g (0.002 mole) of 2-chloroethyl-p-toluenesulfonate was added and refluxing was continued another 2 hours. The mixture was poured into ice water and extracted with methylene chloride three times. The methylene chloride layers were dried and concentrated on a rotary evaporator. The residue was chromatographed on silica gel, eluting with chloroform. The product was obtained by trituration of fractions 4 and 5 with ether to give crystalline material, m.p. 149°-151°. Analysis by IR, NMR and CHN microanalysis indicated the product in a purity of about 85%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1>>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)[CH:29]=[CH:30]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCOCC1
Yield: 60.5 %

Procedure:
Using an analogous procedure to that described for Example 120, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxyindole (95 mg, 0.71 mmol) to give 4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (155 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C@@H:16]1[CH2:20]OS(=O)(=O)[N:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:20])[NH:17][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Agent: Cl
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](C)Nc2ccccn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.16 grams (46.6 millimoles) of 1-(2-methoxyphenyl)piperazine in one portion was added under argon to a solution of 10 grams (46.6 millimoles) of (R)-4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide in 200 milliliters of acetonitrile. The mixture became yellow. After ½ hour, the reaction mixture was heated to 50° C. for 1 hour and then stirred at room temperature overnight Then dilute hydrochloric acid was added. The mixture was washed with ethyl acetate, basified to pH 12 and extracted twice with ethyl acetate. The organic phases were washed with brine, dried (Mg SO4) and subjected to evaporation to give 12.053 grams of the title compound which was purified by columning in the system ethyl ether/hexane (1:1) Al2O3 to afford 9.96 grams of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[CH:18]([N:31]1[CH2:34][C:33](OS(C)(=O)=O)([CH3:35])[CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[CH:18]([N:31]1[CH2:34][C:33]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)([CH3:35])[CH2:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
A mixture of (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 172 mmol), methansulfonic acid 1-benzhydryl-3-methylazetidin-3-yl ester (Preparation #14, Step B, 95 g, 258 mmol) and K2CO3 (47.6 g, 344 mmol) in iPrOH (1 L) was stirred at 90° C. for 16 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in water (1 L) and extracted with EtOAc (3×500 mL). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (eluting with 30-60% EtOAc in petroleum ether) to give (R)-6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (31 g, 38%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (s, 1H), 7.45-7.40 (m, 4H), 7.30-7.26 (m, 4H), 7.22-7.16 (m, 2H), 6.78 (d, J=9.0 Hz, 1H), 6.08-6.02 (m, 2H), 4.64-4.57 (t, J=6.8 Hz, 1H), 4.53-4.41 (d, J=14.8 Hz, 3H), 3.30 (m, 2H), 3.15 (m, 2H), 1.65 (s, 3H), 1.46 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 1) Rt=4.36 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[N:11]([OH:19])[C:10]2=[O:20])=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:19][N:11]1[C:12](=[O:18])[C:13]2[S:17][CH:16]=[CH:15][C:14]=2[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[CH:3][CH:4]=2)[C:10]1=[O:20]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=c1c2sccc2n(Cc2ccc(Cl)nc2)c(=O)n1O
Product: O=c1c2sccc2n(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2)c(=O)n1O

Procedure:
The title compound was prepared from 1-(6-chloro-pyridin-3-ylmethyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) and 4-trifluoromethoxy phenylboronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.85 (bs, 1H), 8.72 (d, 1H, J=1.8 Hz), 8.17 (d, 1H, J=8.7 Hz), 8.16 (d, 1H, J=5.5 Hz), 7.97 (d, 1H, J=8.1 Hz), 7.82 (dd-1H, J=1.8, 8.1 Hz), 7.47 (d, 2H, J=8.7 Hz), 7.45 (d, 1H, J=5.5 Hz), 5.40 (s, 2H); Electrospray MS: 436 (M+H); retention time: 2.84 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[N:10](C)[C:11]([S:20][CH3:21])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=[C:11]([S:20][CH3:21])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Product: CSc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1

Procedure:
5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-3H-pyrimidin-4-one (0.327 g, 1 mmol) and 5 ml of POCl3 in a 15-ml r.b.flask with a stir bar was stirred at 120° C. for 16 h. The remaining POCL3 was evaporated in vacuo. The dark brown residue was mixed with ice-water. The resulting acidic dark brown solution was neutralized to pH 7-8 with sat'd NaHCO3 and extracted by EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml) and dried over Na2SO4. 4-chloro-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)pyrimidine was isolated by flash chromatography with 50% EtOAc in hexane; MS: m/z (M+H)+ 332; C16H11ClFN3S requir.331.8.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][Si:12]([CH3:16])([CH3:15])[C:13]#[CH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][Si:12]([C:13]#[C:14][C:3]1[CH:4]=[C:5]2[N:10]=[CH:9][NH:8][C:6]2=[N:7][CH:2]=1)([CH3:16])[CH3:15]
Reactant: Brc1ccc2nc[nH]c2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc2[nH]cnc2c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.2 g (6.1 mmol) 5-bromo-3H-imidazo[4,5-b]pyridine and 1.2 mL (8.4 mmol) 1-trimethylsilyl-ethyne using 34 mg (0.18 mmol) CuI, 159 mg (0.61 mmol) triphenylphosphine, 128 mg (0.18 mmol) PdCl2(PPh3)2 and 10.1 mL (72.7 mmol) triethylamine in 10 mL dry THF. The formed precipitate is filtered off and the product is purified by RP-HPLC using an ACN/H2O gradient. Yield: 606 mg (46%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O:34][CH2:35][CH3:36])C>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:1]4[CH2:2][CH2:3][CH2:36][C:35](=[O:34])[C:5]=4[CH3:6])=[CH:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CCOCC
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)OC1(C)C
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1=O

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 19, Step B (0.350 g, 0.87 mmol) and 3-oxo-2-methyl-cylclohex-1-en-1-yl trifluoromethanesulfonate (0.248 g, 0.96 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 20 to 50% ethyl acetate in hexane afforded a light yellow oil. The oil thus isolated was dissolved in boiling diethyl ether and precipitated by addition of petroleum ether. The precipitate was filtered and dried to afford the title compound (0.297 g) as a white solid, m.p. 95–97° C.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:23]([O:22][C:20](=[O:27])[NH:21][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Cl:19])=[CH:4][N:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(N)=O
Reactant: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Cl)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ncc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 70 °C
Yield: 121.1 %

Procedure:
A mixture of 4-bromo-7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (400 mg, 1.06 mmol), tert-butyl carbamate (619 mg, 5.3 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), Xantphos (61 mg, 0.1 mmol) and potassium phosphate tribasic (449 mg, 2.1 mmol) in toluene (10 mL) and water (2.0 mL) was purged with argon and heated at 70° C. for 3 hours. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was washed with water and brine, dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (531 mg, contaminated with residual tert-butyl carbamate). LCMS (Method D): RT=3.76 min, m/z: 413 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([O:17][CH3:18])=[N:11]2.[OH-].[Na+].C(O)(=O)C>CO.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:24][CH:25]=1)=[C:8]2[CH3:31]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A solution of [8-chloro-2-methoxy-4-methyl-3-(4-pyrazol-1-yl-benzyl)quinolin-5-yloxy]acetic acid methyl ester (0.37 g) in methanol (7.0 mL) and water (0.7 mL) was treated with 5.0M aqueous sodium hydroxide solution (0.32 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was crystallised from methanol to give title compound as a white solid (0.18 g).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=1)([O-])=O>C(O)C.[Fe]>[CH3:10][N:9]([C:8]1[CH:12]=[CH:13][C:5]([NH2:2])=[CH:6][CH:7]=1)[CH3:11]
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitroaniline (1.83 g; 13.24 mmol) is added portionwise to cooled (T=+4° C.) formic acid (3 mL; 66.2 mmol). Formaldehyde (37 wt. % solution in water; 2.72 mL; 29.13 mmol) is added and the resulting mixture refluxed for 24 h. After cooling at room temperature 6N HCl is added (2.2 mL) and the formed precipitate is filtered off. The filtrate is diluted with 1N NaOH (5 mL) and extracted with CH2Cl2 (3×20 mL); the organic collected extracts are dried over Na2SO4 and evaporated under vacuum to give a solid residue which, after treatment with a mixture of diisopropyl ether/acetone 1:1 and filtration, gives 4-nitro-N,N-dimethylaniline as a yellow powder (1.65 g; 9.93 mmol). Iron powder (2.145 g; 38.3 mmol) and 37% HCl (28 μl) are suspended in 96% ethyl alcohol (35 mL) and the mixture refluxed for 30′; at the end 4-nitro-N,N-dimethylaniline (0.64 g; 3.84 mmol) is added and the mixture left under reflux and stirring for 2 h. The hot mixture is filter over a Celite pad and, after cooling at room temperature, the filtrate is evaporated under vacuum. The oily residue is diluted with CH2Cl2 (25 mL) and washed with 1N NaOH (3×25 mL), dried over Na2SO4 and evaporated under vacuum to give 4-(N,N-dimethylamino)aniline as pale yellow oil (0.44 g; 3.26 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[Br:26]C1C=CN=CC=1>>[Br:26][C:14]1[C:13]2[C:17](=[CH:18][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:11][CH:12]=2)[N:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4ccncc4)c3c2)c1
Reactant: Brc1ccncc1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)c1

Procedure:
The target compound was prepared as in Example 1 using 6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indole (70 mg, 0.222 mmol) and 4-bromopyridine hydrochloride (40 mg, 0.222 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23]>O1CCCC1>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])([O:15][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: C=CCNCC=C
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCN(CC=C)OP(=O)(CN(CC(=O)OCC)C(=O)C(F)(F)F)ON(CC=C)CC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 25 ml. of tetrahydrofuran was added diallylamine (4.07 g, 0.042 mole) in 50 ml. of tetrahydrofuran. The mixture was stirred at room temperature overnight and was then filtered and the filtrate concentrated in vacuo. The residue was dissolved in ether, washed with water, 10% HCl, water, dried over MgSO4, and concentrated in vacuo. The residue was extracted with petroleum ether, and by concentrating the petroleum ether soluble material, ethyl N-trifluoroacetyl-N-(bis(diallylamino)phosphonomethyl)glycinate was obtained as a light yellow oil, ND =1.4536.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33]>>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:31][C:32]([NH2:34])=[O:33])[C@@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NC(=O)CI
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1CC[C@@H](NCC(N)=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared using the amine from Example 28 and iodoacetamide using essentially the same procedure as Example 10. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>>[Br:24][CH2:25][C:26]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)=[O:27]
Reactant: O=C(Cl)CBr
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21

Procedure:
The process is carried out as in preparation 1.1 above, using compound from Example 72A, 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and bromoacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[NH:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[N:6][C:5]=2[N:21]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:21][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)[nH]c(=O)c2s1
Solvent: CN(C)c1ccccc1
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reaction time: 0.33 h
Yield: 31 %

Procedure:
The product of step (c) (10.0 g) was suspended in phosphoryl chloride (55 ml). N,N-dimethylaniline (5.5 ml) added slowly and reaction mixture heated at reflux for 2 hours. Allowed to cool, then poured on to ice with vigorous stirring; temperature was not allowed to go above 45° C. (ice added). After approximately 20 minutes the temperature stabilized at 30° C. The solid that formed was collected by filtration and washed with water. Purified by column chromatography (EtOAc to 5% MeOH in EtOAc) to give 3.34 g of product. 31% yield.