Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:34](=[N:37]O)([CH3:36])[CH3:35].O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][N:37]=[C:34]([CH3:36])[CH3:35])=[O:9])[C:5]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)O)n1
Reactant: CC(C)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)nc(Oc2ccc(N)nc2C(=O)ON=C(C)C)n1
Yield: 58.3 %

Procedure:
1.5 g (5 mmol) of 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinic acid, 0.8 g (5 mmol) of carbonyldiimidazole and 0.25 g (3 mmol) of N-isopropylidenehydroxylamine were stirred and refluxed in dichloromethane for 4 hours. After completion of the reaction, the reaction mixture was poured into water, and the dichloromethane layer was separated, washed with water and dried. Then, the solvent was distilled off under reduced pressure. The residual oily product was purified by column chromatography to obtain the desired product as colorless transparent crystals.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=O)[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=CCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: C[C@@H](N)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](CO)NCCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 73 %

Procedure:
The titled compound was prepared from N-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example 3(ii)) (0.10 g), (R)-2-aminopropanol (0.046 g) and sodium cyanoborohydride (0.020 g) in methanol (3 ml) and acetic acid (0.1 ml) by the method of Example 3(iii). The product was purified by chromatography on silica gel eluting with 0.7M anhydrous ammonia in methanol:ethyl acetate (1:5) to afford the titled compound as an oil (0.085 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:15][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][OH:7])=[CH:18][CH:17]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)cc1

Procedure:
(Formula II, R1=tert-butyldimethylsilyloxymethylphenyl, R2=4-tert-butyldimethylsilyloxymethylbenzyl). Methyl 4-(hydroxymethyl)benzoate was treated with tert-butyldimethylsilyl chloride using the general procedure described in Journal of the American Chemical Society, 1972, 94, 6190. The resulting product was reduced with lithium aluminium hydride to afford 4-(tert-butyldimethylsilyloxymethyl)benzyl alcohol. This alcohol was converted into the required compound using Method C. 1H NMR (CCl4) δ 0.08 (32H, s), 0391 (18H, s), 4.22 (1H, d, J 2 Hz), 4.68 (5H, br s), 4.90 (2H, a), 7.1-7.6 (8H, m); MS (CH4) 483 (M+−CH3, 52%), 133 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C(NCC)C>[Cu]I.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.CN(C=O)C>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Reactant: COc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Temperature: 120 °C
Yield: 10.7 %

Procedure:
A mixture of (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.027 mmol), 4-bromo-2-methoxypyridine (10 mg, 2 equiv), CuI (0.5 mg, 10% mol), Pd(PPh3)2Cl2 (1.9 mg, 10% mol), diethylamine (1 mL), dry DMF (1 mL) was degassed, refilled with nitrogen gas (3×). The mixture was then heated in the microwave for 45 min at 120° C. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((2-methoxypyridin-4-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.4 mg). LC-MS Method 1 tR=1.92 min, m/z 485 (M+1); 1H NMR (CD3OD) 7.41-7.27 (m, 7H), 6.97 (m, 4H), 5.55 (q, 1H), 3.92 (s, 3H), 3.04 (m, 1H), 2.49 (m, 2H), 2.21 (m, 1H), 2.14 (s, 2H), 1.53 (d, 3H), 1.28 (t, 1H), 1.26 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:20])=[O:19].[F:30]C1C=CC(CCN)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:18]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)(=[O:19])=[O:20]
Reactant: NCCc1ccc(F)cc1
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccccc3)c2)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccc(F)cc3)c2)cc1

Procedure:
The title compound is prepared as described for 2-chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide, except using 4-fluoro-phenethylamine. 1H NMR (CDCl3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.60 (m, 1H), 7.08 (m, J=8 Hz, 2H), 7.00 (m, 3H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C22H19ClFNO4S: C, 58.99; H, 4.28; N, 3.13. Found: C, 58.58; H, 4.33; N, 3.12. MS (m/z): 448.0 (M+1)−.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(NC(C)C)(C)C>O1CCCC1.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.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a degassed solution of the above ester (392 mg, 0.707 mmol), N-propargylmorpholine (176 mg, 1.41 mmol) and diisopropyl amine (0.466 mL, 3.3 mmol) in anhydrous tetrahydrofuran (11 mL), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and copper(I) iodide (12.0 mg, 0.063 mmol) were added. The reaction mixture was stirred at ambient temperature for 7 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[OH:36].[Na+].Cl[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.[Ni].ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:36][C@H:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=Cc2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: O=C([O-])O
Agent: [Ni]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1

Procedure:
Mixture: 66.7 g 150 mmol) of 3,3'-dibenzyloxy-4,4'-dimethoxystilbene, 1500 ml of dichloromethane, 1500 ml of sodium hydrogen carbonate solution, 667 mg (1.5 mmol) of nickel-salene, 1.334 g (4.3 mmol) of benzyltributylammonium chloride, 250 ml of sodium hypochlorite solution (13% active chlorine).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]1([NH:11][C:12](=[S:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)C.ICC>ClCCl>[CH2:2]([S:19][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: S=C(Nc1ccccc1)c1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Solvent: ClCCl
Product: CCSC(=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 3.2 g of sodium ethoxide, 10 g of N-phenylthiobenzamide, and 60 mL of ethanol were put in a 300 mL three-neck flask, and this mixed solution was stirred at room temperature for 1 hour. Then, 3.7 mL of iodoethane was added to this mixed solution, and heated and stirred at 60° C. for 6 hours to be reacted. After the reaction, ethanol was distilled off under a reduced pressure to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the resulting organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated, so that N-[(ethylsulfanyl)phenylmethylidene]aniline was prepared (a brown oily substance, crude yield: 110%). The synthetic scheme of Step 1 is shown by (a-5).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCc1ccccc1

Procedure:
Batch size: 11.0 g (34.2 mmol) 2-(7-phenyl-heptyl)-isoindol-1,3-dione and 3.4 g (68.4 mmol) hydrazine.hydrate in 100 ml ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[C:38]([CH3:39])=[C:37]2[C:32]([CH:33]=[C:34]([NH2:40])[CH:35]=[CH:36]2)=[N:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[CH3:29][N:30]1[C:38]([CH3:39])=[C:37]2[C:32]([CH:33]=[C:34]([NH:40][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:10][CH2:11][C:12]5([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]5)[CH2:25][CH2:26]4)[C:5]([CH3:27])=[CH:4][N:3]=3)[CH:35]=[CH:36]2)=[N:31]1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A mixture of tert-butyl 9-((2-chloro-5-methylpyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (1.2 g, 3.0 mmol), 2,3-dimethylindazol-6-amine hydrochloride (896.5 mg, 4.536 mmol), diacetoxypalladium (132.4 mg, 0.5898 mmol), BINAP (370.3 mg, 0.5947 mmol) and dicesium carbonate (2.98 g, 9.15 mmol) was dissolved in anhydrous dioxane (10 mL). The reaction mixture was stirred under microwave irradiation at 150° C. for 2 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (1.04 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2[S:17][C:18]([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 5-methoxy-3-(t-butylthio)indole-2-carboxylate from step 1 in DMF (50 ml) at 0° C. was added sodium hydride (60% suspension in mineral oil 460 mg, 11.5 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and p-chlorobenzyl chloride (1.93 g, 12.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 14 hours and was then poured into H2O (200 ml) and extracted with ethyl acetate. The organic phase was washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (8:1 hexane/ethyl acetate) to provide 4.1 g of ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].CCOC(C)=O.O>CN(C=O)C>[C:15]([O:14][C:12]([N:10]1[CH2:9][CH2:8][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:28][CH2:27][CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[C:5]=2[CH2:11]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)nc(Cl)c2C1
Reactant: NCCc1ccccn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Cl)nc(NCCc3ccccn3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (100 mg, 0.329 mmol) and TEA (0.137 mL, 0.986 mmol) in DMF (1.5 mL) was treated with 2-(2-pyridyl)ethyl amine (40.2 mg, 0.329 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was EtOAc (10 mL) and H2O (10 mL), and extracted with EtOAc (2×10 mL). The combined organic phases were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes to afford the title compound as a pale yellow gum (96 mg, 75%). Data for G-1: 1H NMR (500 MHz, CDCl3) δ 8.524-8.64 (br m, 1H), 7.61-7.69 (br m, 1H), 7.15-7.24 (m, 2H), 6.67-6.89 (br m, 1H), 4.24 (s, 2H), 3.67 (br m, 2H), 3.08 (t, J=9.0 Hz, 2H), 2.75 (br s, 2H), 1.51 (s, 9H); LC/MS: rt=1.35 min, m/z (M+H)=390.1 found; 390.2 calcd.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(Cl)n1

Procedure:
A solution of (3-chloro-benzyl)-carbamic acid tert-butyl ester (458 mg, 1.9 mmol) in DMF (20 mL) was treated with 60% NaH in mineral oil (152 mg, 3.79 mmol). The resulting mixture was stirred at room, temperature until the gas evolution ceased and 2,6-dichloro-pyrazine (282 mg, 1.89 mmol) was added. The reaction mixture was stirred at 80° C. until the LC/MS indicated the reaction was complete. The reaction mixture was cooled and poured into Ethyl Acetate and washed with H2O and brine. The organic layers were combined, dried (Na2SO4), and concentrated to yield the title compound I-4e (199 mg).
Reaction SMILES: CC(C)([S@]([NH:6][C@H:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=1)=O)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:6][C@H:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:9]=[CH:10][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:12][CH:13]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1ccc([C@H](N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Ethyl 4-((R)—((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)phenyl(methyl)phosphinate, 23-b, (9.5 g, 24.1 mmol) was dissolved in HCl/dioxane (100 ml) and the mixture was stirred at room temperature overnight. Then it was concentrated under vacuum and the residue was washed with ethyl acetate to provide the product, 23-c, (7.16 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[NH:20])SC)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]12[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:27]C(=O)O[C:23]2=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[NH:27][C:28]3[C:22]([C:23](=[O:24])[N:20]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CSC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(Nc2nc(=O)c3ccccc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of compound 79.3 (1.5 mmol), isatoic anhydride (1.5 mmol), and Na2CO3 (3.0 mmol) in dioxane (15 mL) was stirred at 100° C. for 8 hours. The solvent was removed and the residue was diluted with 20 mL of water. Subsequently, the suspension was filtered and the white solid was washed sequentially with water and ether, and then dried in vacuo to give {2-[4-(4-oxo-1,4-dihydro-quinazolin-2-ylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (compound 79.4) in 52% yield. 1H NMR (d6-DMSO, 400 MHz): δ 10.77 (s, 1H), 8.60 (s, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.59 (m, 3H), 7.35 (d, J=8.3 Hz, 1H), 7.12-7.20 (m, 3H), 6.86 (s, 1H), 3.09 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz, 2H), 1.34 (s, 9H) ppm; EIMS (m/z): 381.2 (M++H).
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][CH:11]1[O:15][CH:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][CH3:26])[CH:13]([O:27]C(=O)C2C=CC=CC=2)[CH2:12]1)([O:6]CC)=[O:5])C.C[Si](Br)(C)C>CC#N>[OH:27][CH:13]1[CH:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][CH3:26])[O:15][CH:11]([CH:10]=[CH:9][P:4](=[O:3])([OH:6])[OH:5])[CH2:12]1
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(NC)ncnc32)O1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CNc1ncnc2c1ncn2C1OC(C=CP(=O)(O)O)CC1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
Compound 47.1 (277 mg, 0.45 mmol) was dissovled in 4.5 mL anhydrous CH3CN and treated with TMSBr (0.9 mL, 6.8 mmol). The solution was stirred at rt for 3 h, and then concentrated under reduced pressure. The residue was dissolved in NH4OH, stirred for another 2 h, and concentrated under reduced pressure. The residue was subjected to a reverse phase HPLC to give compound 47.2 (97 mg, 51% yield). 1H NMR (D2O, 300 MHz): δ 2.15-2.23 (m, 2H), 3.02 (s, 3H), 4.96 (s, 1H), 5.90-5.95 (m, 1H), 6.02 (d, 1H, J=1.2), 6.39 (m, 1H), 8.09 (s, 1H), 8.17 (s, 1H). 31PNMR: 11.34 ppm. LRMS [M−H]− C12H16N5O5P requires 340.1. Found 340.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:10](O)=[C:5]2[C:4]([CH3:18])=[N:3]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[C:5]=12
Reactant: Cc1nn(C)c2nc(-c3ccccc3)cc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2nc(-c3ccccc3)cc(Cl)c12

Procedure:
73 gms. of 1,3-dimethyl-4-hydroxy-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.31 mol.) are refluxed in 800 ml. of phosphorus oxychloride for 6 hours. The excess phosphorus oxychloride is removed in vacuo and the oily residue is treated with ice-water by which operation the compound becomes solid. The compound is extracted with ether, washed with an aqueous sodium carbonate solution (10%) and again with water. Evaporation of the dried (Na2SO4) and charcoal treated ethereal extract provides 4-chloro-1,3 -dimethyl-6-phenyl-1H-pyrazolo[3,4-b]-pyridine which is washed with absolute ethanol, yield: 55.6 gms. (69.8%) of white product melting at 89°-90° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].Cl>O1CCCC1.C(OCC)(=O)C>[C:23]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCc1ccccc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Methyl 4-(2-aminophenyl)butanoate hydrochloride (7.20 g, 0.037 mol) synthesized by a known method by documents (Synthetic communications, 26(18), 3443 (1996)) and triethylamine (5.06 g, 0.05 mol) were dissolved in tetrahydrofuran (60 ml). Acetyl chloride (3.51 g, 0.045 mol) was added dropwise to the mixture, which was stirred at room temperature for 30 minutes. Ethyl acetate and 1N hydrochloric acid were added to the reaction mixture, and extraction was conducted. The organic layer was washed with water, concentrated and dried. A mixed solution of ethyl acetate-n-hexane (1:1) was added to the residue. The crystallized product was collected by filtration, to give methyl 4-(2-acetylaminophenyl)butanoate (6.40 g) as a white powder.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@H:13](O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:54])C(=O)C1>C(Cl)Cl>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@@H:13]([Cl:54])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of mixture of compound 8 (1.0 g, 2.67 mmol) and PPh3 (1.4 g, 5.34 mmol) in CH2Cl2 (15 mL) was added NCS (1.07 g, 8.01 mmol) portionwise at 0° C. Then the resulting mixture was stirred at rt for 1 h and poured into a silica gel column and eluted with EtOAc-hexanes (1:4) using pressure. The collected right fractions were combined, concentrated, and co-evaporated with CH2Cl2 several times and used next step (1.0 g, 95%).